U.S. patent application number 11/795934 was filed with the patent office on 2008-06-12 for fatty acid-benzenediol derivatives and methods of making and using thereof.
Invention is credited to Colin J. Barrow, Jaroslav A. Kralovec.
Application Number | 20080139649 11/795934 |
Document ID | / |
Family ID | 36992814 |
Filed Date | 2008-06-12 |
United States Patent
Application |
20080139649 |
Kind Code |
A1 |
Barrow; Colin J. ; et
al. |
June 12, 2008 |
Fatty Acid-Benzenediol Derivatives and Methods of Making and Using
Thereof
Abstract
Disclosed are compounds comprising a benzenediol derivative
bound to one or more fatty acids. Also disclosed are nutritional
supplements, pharmaceutical formulations, delivery devices, and
foodstuffs comprising the disclosed compounds. Methods of using the
disclosed compounds and compositions to improve health are also
disclosed.
Inventors: |
Barrow; Colin J.; (Halifax,
CA) ; Kralovec; Jaroslav A.; (Halifax, CA) |
Correspondence
Address: |
NEEDLE & ROSENBERG, P.C.
SUITE 1000, 999 PEACHTREE STREET
ATLANTA
GA
30309-3915
US
|
Family ID: |
36992814 |
Appl. No.: |
11/795934 |
Filed: |
January 17, 2006 |
PCT Filed: |
January 17, 2006 |
PCT NO: |
PCT/IB06/01229 |
371 Date: |
December 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60647545 |
Jan 27, 2005 |
|
|
|
Current U.S.
Class: |
514/546 ;
424/451; 554/229 |
Current CPC
Class: |
C07C 69/587 20130101;
C07C 69/587 20130101; C07C 67/307 20130101; A23L 33/30 20160801;
C07C 67/307 20130101 |
Class at
Publication: |
514/546 ;
554/229; 424/451 |
International
Class: |
A61K 31/22 20060101
A61K031/22; C07C 69/618 20060101 C07C069/618; A61K 9/48 20060101
A61K009/48 |
Claims
1. A compound, comprising Formula I: ##STR00015## wherein R.sup.1
is an unsaturated fatty acid residue; R.sup.2 is H or a fatty acid
residue; and R.sup.3 is, independently, H, OH, alkyl, alkoxide,
alkenyl, or alkynyl.
2. The compound of claim 1, wherein R.sup.1 is an unsaturated fatty
acid residue derived from fish oil.
3. The compound of claim 1, wherein R.sup.1 is an unsaturated fatty
acid residue comprising at least 20 carbon atoms.
4. The compound of claim 1, wherein R.sup.1 is an unsaturated fatty
acid residue comprising at least one pair of methylene interrupted
unsaturated bonds.
5. The compound of claim 1, wherein R.sup.1 is an unsaturated fatty
acid residue derived from an omega-3 fatty acid.
6. The compound of claim 1, wherein R.sup.1 is an unsaturated fatty
acid residue derived from a compound comprising the formula:
##STR00016## wherein R.sup.4 is a C.sub.3-C.sub.40 alkyl or alkenyl
group.
7. The compound of claim 6, wherein R.sup.4 has from 2 to 6 double
bonds.
8. The compound of claim 1, wherein R.sup.1 comprises an
unsaturated fatty acid residue derived from linoleic acid,
linolenic acid, gamma-linolenic acid, arachidonic acid, mead acid,
stearidonic acid, alpha-eleostearic acid, eleostearic acid,
pinolenic acid, docosadienic acid, docosatetraenoic acid,
octadecadienoic acid, octadecatrienoic acid, eicosatetraenoic acid,
or any combination thereof.
9. The compound of claim 1, wherein R.sup.1 is an unsaturated fatty
acid residue derived from eicosapentaenoic acid 20:5.omega.3
(EPA).
10. The compound of claim 1, wherein R.sup.1 is an unsaturated
fatty acid residue derived from docosahexaenoic acid 22:6.omega.3
(DHA).
11. The compound of claim 1, wherein R.sup.1 is an unsaturated
fatty acid residue derived from docosapentaenoic acid 22:5.omega.3
(DPA).
12. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues derived from fish oil.
13. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues comprising at least 20 carbon
atoms.
14. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues comprising at least one pair of
methylene interrupted unsaturated bonds.
15. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues derived from an omega-3 fatty
acid.
16. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues derived from a compound comprising
the formula: ##STR00017## wherein R.sup.4 is a C.sub.3-C.sub.40
alkyl or alkenyl group.
17. The compound of claim 16, wherein R.sup.4 has from 2 to 6
double bonds.
18. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues derived from linoleic acid,
linolenic acid, gamma-linolenic acid, arachidonic acid, mead acid,
stearidonic acid, alpha-eleostearic acid, eleostearic acid,
pinolenic acid, docosadienic acid, docosatetraenoic acid,
octadecadienoic acid, octadecatrienoic acid, eicosatetraenoic acid,
or any combination thereof.
19. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues derived from eicosapentaenoic acid
20:5.omega.3 (EPA), docosahexaenoic acid 22:6.omega.3 (DHA),
docosapentaenoic acid 22:5.omega.3 (DPA), or a combination
thereof.
20. The compound of claim 1, wherein the compound has the Formula
IV ##STR00018## wherein R.sup.3 and each R.sup.6 is an alkyl group
and n is from 1 to 12.
21. The compound of claim 20, wherein each R.sup.3 is a methyl
group and n is 10.
22. The compound of claim 20, wherein R.sup.1 is an unsaturated
fatty acid residue derived from fish oil.
23. The compound of claim 20, wherein R.sup.1 is an unsaturated
fatty acid residue comprising at least 20 carbon atoms.
24. The compound of claim 20, wherein R.sup.1 is an unsaturated
fatty acid residue comprising at least one pair of methylene
interrupted unsaturated bonds.
25. The compound of claim 20, wherein R.sup.1 is an unsaturated
fatty acid residue derived from an omega-3 fatty acid.
26. The compound of claim 20, wherein R.sup.1 is an unsaturated
fatty acid residue derived from eicosapentaenoic acid 20:5.omega.3
(EPA), docosahexaenoic acid 22:6.omega.3 (DHA), docosapentaenoic
acid 22:5.omega.3 (DPA), or a combination thereof.
27. The compound of claim 20, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues derived from fish oil.
28. The compound of claim 20, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues comprising at least 20 carbon
atoms.
29. The compound of claim 20, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues comprising at least one pair of
methylene interrupted unsaturated bonds.
30. The compound of claim 20, wherein R.sup.1 and R.sup.2 are
unsaturated fatty acid residues derived from an omega-3 fatty
acid.
31. The compound of claim 20, wherein each R.sup.3 is a methyl
group, n is 10, and R.sup.1 and R.sup.2 are unsaturated fatty acid
residues derived from fish oil.
32. A compound, comprising Formula I: ##STR00019## wherein R.sup.1
is a fatty acid residue; R.sup.2 is, independently, a H or a fatty
acid residue; and R.sup.3 is, independently, H, OH, alkyl, alkoxyl,
alkenyl, or alkynyl, and wherein the compound is not ##STR00020##
wherein R.sup.5 is a linear or branched alkyl group with 1 to 20
carbon atoms, or an aryl group, optionally substituted with alkyl
from 1 to 6 carbon atoms and X is absent or a CO group.
33. A method for preparing a compound, comprising reacting a
compound comprising Formula III: ##STR00021## wherein R.sup.3 is,
independently, H, OH, alkyl, alkoxyl, alkenyl, or alkynyl with one
or more unsaturated fatty acids or a derivative thereof.
34. The method of claim 33, wherein in the unsaturated fatty acid
derivative is a salt, ester, thioester, amide, acid halide, or
mixed anhydride.
35. The method of claim 33, wherein the unsaturated fatty acid or
derivative thereof is derived from fish oil.
36. The method of claim 33, wherein unsaturated fatty acid or
derivative thereof comprises at least 20 carbon atoms.
37. The method of claim 33, wherein the unsaturated fatty acid or
derivative thereof comprises at least one pair of methylene
interrupted unsaturated bonds.
38. The method of claim 33, wherein the unsaturated fatty acid or
derivative thereof is derived from an omega-3 fatty acid.
39. The method of claim 33, wherein the unsaturated fatty acid or
derivative thereof comprises the formula: ##STR00022## wherein
R.sup.4 is a C.sub.3-C.sub.40 alkyl or alkenyl group.
40. The method of claim 39, wherein R.sup.4 has from 2 to 6 double
bonds.
41. The method of claim 33, wherein the unsaturated fatty acid or
derivative thereof comprises linoleic acid, linolenic acid,
gamma-linolenic acid, arachidonic acid, mead acid, stearidonic
acid, alpha-eleostearic acid, eleostearic acid, pinolenic acid,
docosadienic acid, docosatetraenoic acid, octadecadienoic acid,
octadecatrienoic acid, eicosatetraenoic acid, or a combination
thereof.
42. The method of claim 33, wherein the unsaturated fatty acid or
derivative thereof comprises eicosapentaenoic acid 20:5.omega.3
(EPA), docosahexaenoic acid 22:6.omega.3 (DHA), docosapentaenoic
acid 22:5.omega.3 (DPA), or a combination thereof.
43. The method of claim 33, wherein the compound III has the
formula VI ##STR00023## wherein R.sup.3 and each R.sup.6 is an
alkyl group and n is from 1 to 12.
44. The method of claim 43, wherein each R.sup.3 is a methyl group
and n is 10.
45. The method of claim 43, wherein the unsaturated fatty acid or
derivative thereof is derived from fish oil.
46. The method of claim 43, wherein the unsaturated fatty acid or
derivative thereof comprises at least 20 carbon atoms.
47. The method of claim 43, wherein the unsaturated fatty acid or
derivative thereof comprises at least one pair of methylene
interrupted unsaturated bonds.
48. The method of claim 43, wherein the unsaturated fatty acid or
derivative thereof is derived from an omega-3 fatty acid.
49. The method of claim 43, wherein the unsaturated fatty acid or
derivative thereof comprises eicosapentaenoic acid 20:5.omega.3
(EPA), docosahexaenoic acid 22:6.omega.3 (DHA), docosapentaenoic
acid 22:5.omega.3 (DPA), or a combination thereof.
50. The method of claim 43, wherein each R.sup.3 is a methyl group,
n is 10, and the unsaturated fatty acid or derivative thereof
comprises fish oil.
51. (canceled)
52. A nutritional supplement comprising a compound of claim 1.
53. The nutritional supplement of claim 52, comprising from about
0.05% to 20% by weight of the compound.
54. The nutritional supplement of claim 52, comprising from about
1% to 7.5% by weight of the compound.
55. The nutritional supplement of claim 52, wherein the supplement
comprises up comprises less than pr equal to 100% by weight of the
compound.
56. The nutritional supplement of claim 52, wherein the supplement
is in the form of a tablet, gel-cap, capsule, liquid, or syrup.
57. A delivery device comprising a compound of claim 1.
58-76. (canceled)
77. A pharmaceutical formulation comprising the compound in claim 1
and a pharmaceutical carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
Provisional Application No. 60/647,545, filed Jan. 27, 2005. U.S.
Provisional Application No. 60/647,545 is incorporated by reference
herein in its entirety.
FIELD
[0002] The disclosed matter relates to compounds comprising fatty
acids and benzenediol derivatives, including methods of making and
using such compounds.
BACKGROUND
[0003] Benzenediols are an important class of compounds with varied
properties and uses. For example, one subclass of benzenediols is
ubiquinol, a reduced form of Coenzyme Q. Coenzymes Q are also
called ubiquinones, mitoquinones, or ubidecarerones, and they are
lipophilic, water-insoluble substances involved in electron
transport and energy production in mitochondria. The basic
structure of coenzymes Q comprises a benzoquinone "head" and a
terpinoid "tail." The "head" structure participates in the redox
activity of the electron transport chain. The major difference
among the various coenzymes Q is in the number of isoprenoid units
(5-carbon structures) in the "tail." Coenzymes Q typically contain
from 1 to 12 isoprenoid units in the "tail"; 10 isoprenoid units
are common in animals such as mammals and man.
[0004] Coenzymes Q occur in the majority of aerobic organisms, from
bacteria to plants and animals. Two numbering systems exist for
designating the number of isoprenoid units in the terpinoid "tail":
coenzyme Q.sub.n and coenzyme Q(x), where n refers to the number of
isoprenoid side chains and x refers to the number of carbons in the
terpinoid "tail" and can be any multiple of five. Thus, coenzyme
Q.sub.10 (also termed CoQ.sub.10) refers to a coenzyme Q having 10
isoprenoid units in the "tail." Since each isoprenoid unit has five
carbons, CoQ.sub.10 can also be designated coenzyme Q(50) or
CoQ(50). The name CoQ.sub.n can be used to generally refer to both
the oxidized form and reduced form of the compound; alternatively,
these specific forms can be individually designated CoQ.sub.nred
and CoQ.sub.nox. Chemically, CoQ.sub.10ox is known as
2,3-dimethyoxy-5-methyl-6-decaprenyl-1,4-benzoquinone, and its
structural formula is:
##STR00001##
[0005] CoQ.sub.10 is a model carrier of protons and electrons. It
plays a vital role in the mitochondrial respiratory chain and
oxidative phosphorylation. It was first isolated by researchers
working at the Enzyme Institute of the University of Wisconsin
(Crane, et al., BBA 25:220-1, 1975). Currently, Japanese Kaneka
Corp. supplies 60-70% of CoQ.sub.10 sold in the USA.
[0006] The oxidized form of CoQ.sub.10 (CoQ.sub.10ox) has
anti-atherogenic properties. Deficiencies in CoQ.sub.10ox are
associated with higher incidence of heart failure and other
cardiovascular problems. Although CoQ.sub.10 plays an important
role in the development of cardiovascular disease, there have been
data that suggest that the coenzyme also plays an important role in
the nervous system. For example, CoQ.sub.10 is believed to have
beneficial effects in the prevention and treatment of Parkinson's
disease, mitochondrial myopathies, muscular dystrophy, etc.
[0007] Several attempts have been made to deliver benzenediol
derivatives such as CoQ.sub.10 to a subject. Seizer disclosed a
liquid dietary CoQ.sub.10 supplement based on vegetable oil-water
emulsion. The absorption of CoQ.sub.10 from this formulation was
enhanced (U.S. Pat. No. 6,652,891 to Selzer et al.).
[0008] Herbamed developed a CoQ.sub.10 formulation based on
Emulsome technology that exhibits superior absorption. The product,
called Ultrasome-CoQ.sub.10, was tested on end-stage heart failure
patients awaiting cardiac transplantation at the Rabin Medical
Center and Sorasky Medical Center, both affiliated with Tel-Aviv
University medical school (Berman M, Erman A, Ben-Gal T, Dvir D,
Georghiou G P, Stamler A, Vered Y, Vidne B A, Aravot D. Coenzyme
Q10 in patients with end-stage heart failure awaiting cardiac
transplantation: a randomized, placebo-controlled study. Clin
Cardiol 2004, 27:295-9). The product was found to be three times
more bioavailable than generic CoQ.sub.10. In the double blind
trial, 32 patients awaiting heart transplantation received either
60 mg of the product or placebo for three months. The Ultrasome
group showed significant improvement in a six-minute walk test and
a decrease in dyspnea (New York Heart Association classification),
nocturia, and fatigue, compared to the placebo.
[0009] Natural Health Sciences together with General Nutrition
Centers developed a blend of Pycnogenol, a French maritime pine
bark extract, and CoQ.sub.10 called PycnoQ10. Joint research
executed at Showa Medical University, Tokyo, and State University
of New York suggested that the combination protected 53% of blood
lipids from oxidation compared to 30% when the ingredients were
used separately. The product protected blood vessel integrity,
blood lipid values, circulation, blood pressure, and platelet
function. The activity is believed to be derived from the synergy
of antioxidant properties.
[0010] Horrobin describes a physical mixture of CoQ.sub.10 and
eicosapentaenoic acid (EPA) (Int'l. Pub. No. WO 02/096408 A1).
Sears, et al., describes a composition made of CoQ.sub.10 and
polyunsaturated fatty acids (PUFA) such as docosahexaenoic acid
(DHA), EPA, or linolenic acid, which is intended for the prevention
and/or treatment of mitochondriopathies (U.S. Pat. No. 6,417,233).
Formation of the ester between PUFA and CoQ.sub.10 is not
disclosed. U.S. Pat. Nos. 6,300,377 and 6,441,050 to Chopra
disclose a combination of CoQ.sub.10 with a polysorbate surfactant,
which can also be mixed with other active materials such as omega-3
fatty acids.
[0011] In light of the numerous health benefits associated with
benzenediol derivatives such as CoQ.sub.10, what is needed in the
art are new compounds and compositions that can be used to supply
such benzenediol derivatives to subjects. Further, what are also
needed are new methods of preparing and using such compounds and
compositions. The compounds, compositions, and methods disclosed
herein meet these needs and other needs.
SUMMARY
[0012] In accordance with the purposes of the disclosed materials,
compounds, compositions, articles, and methods, as embodied and
broadly described herein, the disclosed subject matter, in one
aspect, relates to compounds and compositions and methods for
preparing and using such compounds and compositions. In another
aspect, the disclosed subject matter relates to compounds
comprising Formula I:
##STR00002##
wherein R.sup.1 is an unsaturated fatty acid residue, R.sup.2 is H
or a fatty acid residue, and R.sup.3 is, independently, H, OH,
alkyl, alkoxide, alkenyl, or alkynyl. In a further aspect,
disclosed herein are nutritional supplements, food stuffs, and
pharmaceutical formulations comprising such compounds. In still
another aspect, the disclosed subject matter relates to methods of
preparing such compounds and compositions. Still further, the
disclosed subject matter relates to microcapsules containing such
compounds and compositions and to methods of preparing the
microcapsules. In yet another aspect, the disclosed subject matter
relates to methods of using the described compounds and
compositions.
[0013] Additional advantages will be set forth in part in the
description that follows, and in part will be obvious from the
description, or may be learned by practice of the aspects described
below. The advantages described below will be realized and attained
by means of the elements and combinations particularly pointed out
in the appended claims. It is to be understood that both the
foregoing general description and the following detailed
description are exemplary and explanatory only and are not
restrictive.
BRIEF DESCRIPTION OF FIGURES
[0014] The accompanying Figures, which are incorporated in and
constitute a part of this specification, illustrate several aspects
described below.
[0015] FIG. 1 is flow injection analysis of a CoQ.sub.10 fatty acid
conjugate prepared according to Examples 4-6.
[0016] FIG. 2 is an ESI mass spectrum obtained from total ion
current resulting from flow injection analysis of a CoQ.sub.10
fatty acid conjugate that was prepared according to Examples
4-6.
[0017] FIG. 3 is a fragmentation spectrum resulting from selected
precursor anions (882.7, 1167.0, and 1193.0) resulting from MS of
CoQ.sub.10 fatty acid conjugate that was prepared according to
Examples 4-6.
DETAILED DESCRIPTION
[0018] The materials, compounds, compositions, articles, and
methods described herein may be understood more readily by
reference to the following detailed description of specific aspects
of the disclosed subject matter and the Examples included therein
and to the Figures.
[0019] Before the present materials, compounds, compositions,
articles, and methods are disclosed and described, it is to be
understood that the aspects described below are not limited to
specific synthetic methods or specific reagents, as such may, of
course, vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular aspects only and
is not intended to be limiting.
[0020] Also, throughout this specification, various publications
are referenced. The disclosures of these publications in their
entireties are hereby incorporated by reference into this
application in order to more fully describe the state of the art to
which the disclosed matter pertains. The references disclosed are
also individually and specifically incorporated by reference herein
for the material contained in them that is discussed in the
sentence in which the reference is relied upon.
GENERAL DEFINITIONS
[0021] In this specification and in the claims that follow,
reference will be made to a number of terms, which shall be defined
to have the following meanings:
[0022] Throughout the description and claims of this specification
the word "comprise" and other forms of the word, such as
"comprising" and "comprises," means including but not limited to,
and is not intended to exclude, for example, other additives,
components, integers, or steps.
[0023] As used in the description and the appended claims, the
singular forms "a," "an," and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "a compound" includes mixtures of two or more such
compounds, reference to "an unsaturated fatty acid" includes
mixtures of two or more such unsaturated fatty acids, reference to
"the microcapsule" includes mixtures of two or more such
microcapsules, and the like.
[0024] "Optional" or "optionally" means that the subsequently
described event or circumstance can or cannot occur, and that the
description includes instances where the event or circumstance
occurs and instances where it does not.
[0025] Ranges can be expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, another aspect includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by use of the
antecedent "about," it will be understood that the particular value
forms another aspect. It will be further understood that the
endpoints of each of the ranges are significant both in relation to
the other endpoint, and independently of the other endpoint. It is
also understood that there are a number of values disclosed herein,
and that each value is also herein disclosed as "about" that
particular value in addition to the value itself. For example, if
the value "10" is disclosed, then "about 10" is also disclosed. It
is also understood that when a value is disclosed then "less than
or equal to" the value, "greater than or equal to the value" and
possible ranges between values are also disclosed, as appropriately
understood by the skilled artisan. For example, if the value "10"
is disclosed, then "less than or equal to 10" as well as "greater
than or equal to 10" is also disclosed. It is also understood that
throughout the application data are provided in a number of
different formats and that these data represent endpoints and
starting points and ranges for any combination of the data points.
For example, if a particular data point "10" and a particular data
point "15" are disclosed, it is understood that greater than,
greater than or equal to, less than, less than or equal to, and
equal to 10 and 15 are considered disclosed as well as between 10
and 15. It is also understood that each unit between two particular
units are also disclosed. For example, if 10 and 15 are disclosed,
then 11, 12, 13, and 14 are also disclosed.
[0026] References in the specification and concluding claims to
parts by weight of a particular element or component in a
composition denotes the weight relationship between the element or
component and any other elements or components in the composition
or article for which a part by weight is expressed. Thus, in a
compound containing 2 parts by weight of component X and 5 parts by
weight component Y, X and Y are present at a weight ratio of 2:5,
and are present in such ratio regardless of whether additional
components are contained in the compound.
[0027] A weight percent of a component, unless specifically stated
to the contrary, is based on the total weight of the formulation or
composition in which the component is included.
[0028] As used herein, the term "substituted" is contemplated to
include all permissible substituents of organic compounds. In a
broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic, and
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
below. The permissible substituents can be one or more and the same
or different for appropriate organic compounds. For purposes of
this disclosure, the heteroatoms, such as nitrogen or oxygen, can
have hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valencies of
the heteroatoms. This disclosure is not intended to be limited in
any manner by the permissible substituents of organic compounds.
Also, the terms "substitution" or "substituted with" include the
implicit proviso that such substitution is in accordance with
permitted valence of the substituted atom and the substituent, and
that the substitution results in a stable compound, e.g., a
compound that does not spontaneously undergo transformation such as
by rearrangement, cyclization, elimination, etc.
[0029] The term "alkyl" as used herein is a branched or unbranched
saturated hydrocarbon group of 1 to 40 carbon atoms, such as
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,
t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl,
tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl
group can also be substituted or unsubstituted. The alkyl group can
be substituted with one or more groups including, but not limited
to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl,
aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy,
ketone, nitro, silyl, sulfo-oxo, or thiol, as described below.
[0030] The term "alkoxy" or "alkoxide" as used herein is an alkyl
group bound through a single, terminal ether linkage; that is, an
"alkoxy" group may be defined as --OA where A is alkyl as defined
above.
[0031] The term "alkenyl" as used herein is a hydrocarbon group of
from 2 to 40 carbon atoms with a structural formula containing at
least one carbon-carbon double bond. Asymmetric structures such as
(AB)C.dbd.C(DE) are intended to include both the E and Z isomers
(cis and trans). This may be presumed in structural formulae herein
wherein an asymmetric alkene is present, or it may be explicitly
indicated by the bond symbol C.dbd.C. The alkenyl group can be
unsubstituted or substituted with one or more groups including, but
not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl,
aryl, aldehyde, amino, carboxylic acid, ester, ether, halide,
hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol, as described
below.
[0032] The term "alkynyl" as used herein is a hydrocarbon group of
2 to 40 carbon atoms with a structural formula containing at least
one carbon-carbon triple bond. The alkynyl group can be
unsubstituted or substituted with one or more groups including, but
not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl,
aryl, aldehyde, amino, carboxylic acid, ester, ether, halide,
hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol, as described
below.
[0033] The term "aryl" as used herein is a group that contains any
carbon-based aromatic group including, but not limited to, benzene,
naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The
term "aryl" also includes "heteroaryl," which is defined as a group
that contains an aromatic group that has at least one heteroatom
incorporated within the ring of the aromatic group. Examples of
heteroatoms include, but are not limited to, nitrogen, oxygen,
sulfur, and phosphorus. The aryl group can be substituted or
unsubstituted. The aryl group can be substituted with one or more
groups including, but not limited to, alkyl, halogenated alkyl,
alkoxy, alkenyl, alkynyl, aryl, aldehyde, amino, carboxylic acid,
ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, or
thiol as described herein.
[0034] Unless stated to the contrary, a formula with chemical bonds
shown only as solid lines and not as wedges or dashed lines
contemplates each possible isomer, e.g., each enantiomer and
diastereomer, and a mixture of isomers, such as a racemic or
scalemic mixtures.
[0035] As used herein, by a "subject" is meant an individual. Thus,
the "subject" can include domesticated animals (e.g., cats, dogs,
etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.),
laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.),
and birds. "Subject" can also include a mammal, such as a primate
or a human.
[0036] The term "increase," or other forms of increase, such as
"increasing," refers to an increase in an event or characteristic
above basal levels, e.g., as compared to a control. The terms
"reduces" or "lowers," or other forms the words, such as
"reducing," "reduction," or "lowering," refers to a decrease in an
event or characteristic below basal levels, e.g., as compared to a
control. By "control" is meant either a subject, organ, tissue, or
cell lacking a disease or injury, or a subject, organ, tissue, or
cell in the absence of a particular variable such as a therapeutic
agent. A subject, organ, tissue, or cell in the absence of a
therapeutic agent can be the same subject, organ, tissue, or cell
before or after treatment with a therapeutic agent or can be a
different subject, organ, tissue, or cell in the absence of the
therapeutic agent. Comparison to a control can include a comparison
to a known control level or value known in the art. Thus, basal
levels are normal in vivo or in vitro levels prior to, or in the
absence of, the addition of an agent (e.g., a therapeutic agent) or
another molecule.
[0037] By "prevent" or other forms of prevent, such as "preventing"
or "prevention," is meant to stop a particular event or
characteristic, to stabilize or delay the development or
progression of a particular event or characteristic, or to minimize
the chances that a particular event or characteristic will occur.
Prevention does not require comparison to a control as it is
typically more absolute than, for example, reduce or lower. As used
herein, something could be reduced or lowered but not prevented,
but something that is reduced or lowered could also be prevented.
Likewise, something could be prevented but not reduced or lowered,
but something that is prevented could also be reduced or lowered.
It is understood that where reduce, lowered, or prevent are used,
unless specifically indicated otherwise, the use of the other two
words is also expressly disclosed. Thus, if lowering cholesterol
levels is disclosed, then reducing and preventing cholesterol
levels are also disclosed, and the like.
[0038] By "treat" or other forms of treat, such as "treated" or
"treatment," is meant to administer a composition disclosed herein
or to perform a method disclosed herein in order to reduce or
prevent a particular characteristic or event (e.g., mitochondrial
disease).
[0039] Reference will now be made in detail to specific aspects of
the disclosed materials, compounds, compositions, articles, and
methods, examples of which are illustrated in the accompanying
Examples and Figures.
Materials
[0040] Disclosed herein are materials, compounds, compositions, and
components that can be used for, can be used in conjunction with,
can be used in preparation for, or are products of the disclosed
methods and compositions. These and other materials are disclosed
herein, and it is understood that when combinations, subsets,
interactions, groups, etc. of these materials are disclosed that
while specific reference of each various individual and collective
combinations and permutation of these compounds may not be
explicitly disclosed, each is specifically contemplated and
described herein. For example, if a compound is disclosed and a
number of modifications that can be made to a number of components
or residues of the compound are discussed, each and every
combination and permutation that are possible are specifically
contemplated unless specifically indicated to the contrary. Thus,
if a class of components or residues A, B, and C are disclosed as
well as a class of components or residues D, E, and F, and an
example of a combination compound A-D is disclosed, then even if
each is not individually recited, each is individually and
collectively contemplated. Thus, in this example, each of the
combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are
specifically contemplated and should be considered disclosed from
disclosure of A, B, and C; D, E, and F; and the example combination
A-D. Likewise, any subset or combination of these is also
specifically contemplated and disclosed. Thus, for example, the
sub-group of A-E, B-F, and C-E are specifically contemplated and
should be considered disclosed from disclosure of A, B, and C; D,
E, and F; and the example combination A-D. This concept applies to
all aspects of this disclosure including, but not limited to, steps
in methods of making and using the disclosed compositions. Thus, if
there are a variety of additional steps that can be performed it is
understood that each of these additional steps can be performed
with any specific aspect or combination of aspects of the disclosed
methods, and that each such combination is specifically
contemplated and should be considered disclosed.
[0041] Certain materials, compounds, compositions, and components
disclosed herein can be obtained commercially or can be readily
synthesized using techniques generally known to those of skill in
the art. For example, the starting materials and reagents used in
preparing the disclosed compounds and compositions are either
available from commercial suppliers such as Aldrich Chemical Co.,
(Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher
Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are
prepared by methods known to those skilled in the art following
procedures set forth in references such as Fieser and Fieser's
Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,
1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and
Supplementals (Elsevier Science Publishers, 1989); Organic
Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's
Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and
Larock's Comprehensive Organic Transformations (VCH Publishers
Inc., 1989).
Quinone Derivative-Fatty Acid Compounds
[0042] Disclosed herein, in one aspect, are compounds that comprise
Formula I:
##STR00003##
wherein R.sup.1 is an unsaturated fatty acid residue, R.sup.2 is H
or a fatty acid residue, and R.sup.3 is, independently, H, OH,
alkyl, alkoxide, alkenyl, or alkynyl. The term "residue" as used
herein refers to the moiety that is the resulting product of the
specified chemical species in a particular reaction scheme or
subsequent formulation or chemical product, regardless of whether
the moiety is actually obtained from the specified chemical
species. For example, an "unsaturated fatty acid residue" refers to
the moiety which results when an unsaturated fatty acid
participates in a particular reaction (e.g., the residue can be an
unsaturated fatty acyl group RCO-- or acyloxy group RCOO--). It is
understood that this moiety can be obtained by a reaction with a
species other than the specified unsaturated fatty acid, for
example, by a reaction with an unsaturated fatty acid halide,
ester, thioester, amide, or anhydride. According to the methods
disclosed herein, compounds comprising Formula I and compositions
comprising such compounds can be administered to a subject and
provide numerous health benefits, as described more fully
below.
[0043] Many fatty acids are healthy oils that can serve as suitable
vehicles for delivering various nutraceuticals such as vitamins,
phytosterols, minerals, metals, trace elements, and particularly
molecules like coenzymes, such as CoQ.sub.10. This can be achieved
either by a simple physical mixing, sometimes involving
technologies such as nanoparticling, or by a chemical bond. The use
of oils and their concentrates with proven health benefits, such as
those with a high content of omega-3 fatty acids, can add to the
functionality of the product. The product can then become
bi-functional by combining both the activity of the original
substance to be delivered (e.g., CoQ.sub.10), with well known
cardiovascular benefits of healthy oils (e.g., omega-3 fatty
acids). (See Dyrberg, et al., In: .omega.-3 Fatty Acids: Prevention
and Treatment of Vascular Disease, Kristensen, et al., eds., Bi
& Gi Publ., Verona-Springer-Verlag, London, pp. 217-26, 1995;
O'Keefe and Harris, Am J Cardiology 85:1239-41, 2000, which are
incorporated by reference herein for their teachings of fatty acids
and omega-3 fatty acids). Therefore, the disclosed compounds and
compositions can be beneficial because they combine
benzenediol-derivatives with fatty acids (e.g., those derived from
fish oils and those containing omega-3 fatty acids).
[0044] R.sup.1 and R.sup.2
[0045] General Fatty Acids and Residues
[0046] The disclosed compounds can comprise one or more fatty acids
or residues thereof (e.g., R.sup.1 and R.sup.2 in Formula I). By
"fatty acid" is meant a carboxylic acid with at least 10 carbon
atoms. In one aspect, the fatty acids and residues thereof can
comprise at least 10, at least 12, at least 14, at least 16, at
least 18, or at least 20 carbon atoms. In some specific examples,
the fatty acids and residues thereof can contain 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45
carbon atoms, where any of the stated values can form an upper or
lower endpoint when appropriate. In other examples, the fatty acids
and residues thereof can comprise a mixture of fatty acids and
residues thereof having a range of carbon atoms. For example, the
fatty acids and residues thereof can comprise from about 10 to
about 40, from about 12 to about 38, from about 14 to about 36,
from about 16 to about 34, from about 18 to about 32, or from about
20 to 30 carbon atoms.
[0047] The fatty acids and residues thereof suitable for uses
disclosed herein can be saturated, unsaturated, or a mixture of
saturated and unsaturated fatty acids. By "saturated" is meant that
the molecule or residue contains no carbon-carbon double or triple
bounds. By "unsaturated" is meant that the molecule or residue
contains at least one carbon-carbon double or triple bond. In one
aspect, the substituent R.sup.1 in Formula I can be an unsaturated
fatty acid residue and the substituent R.sup.2 can be either H, an
unsaturated fatty acid residue, or a saturated fatty acid
residue.
[0048] The fatty acids and residues thereof that can be used in the
disclosed compounds and methods can be derived from any source. In
one specific example, the fatty acids and residues thereof can be
derived from fish oil. Such oils typically contain mixtures of
saturated and unsaturated fatty acids, but can be processed to
result in a particular mixture of fatty acids (e.g., containing all
saturated, all unsaturated, mixtures of both, or mixtures with
fatty acids of a certain chain length or range of chain lengths).
Any fish oil can be used in the disclosed compounds and methods.
Specific examples of suitable fish oils include, but are not
limited to, Atlantic fish oils, Pacific fish oils, Mediterranean
fish oils, light pressed fish oil, alkaline treated fish oil, heat
treated fish oil, light and heavy brown fish oil, tuna oil, sea
bass oil, halibut oil, spearfish oil, barracuda oil, cod oil,
menhaden oil, sardine oil, anchovy oil, capelin oil, Atlantic cod
oil, Atlantic herring oil, Atlantic mackerel oil, Atlantic menhaden
oil, salmonids oil, shark oil, and the like.
[0049] Saturated Fatty Acids
[0050] Any saturated fatty acid or residue thereof can be used in
the compounds and methods disclosed herein, as R.sup.2 in Formula I
for example. Examples of specific saturated fatty acids and
residues thereof that are suitable for the compounds and methods
disclosed herein include, but are not limited to, capric acid
(C10), lauric acid (C12), myristic acid (C14), palmitic acid (C16),
margaric acid (C17), stearic acid (C18), arachidic acid (C20),
behenic acid (C22), lignoceric acid (C24), cerotic acid (C26),
montanic acid (C28), and melissic acid (C30), including branched
and substituted derivatives thereof.
[0051] Unsaturated Fatty Acids
[0052] The unsaturated fatty acids and residues thereof that are
suitable for the compounds and methods disclosed herein, as R.sup.1
and R.sup.2 in Formula I for example can comprise at least one
unsaturated bond (i.e., a carbon-carbon double or triple bond). In
one example, the unsaturated fatty acids and residues thereof can
comprise at least 2, at least 3, at least 4, at least 5, at least
6, at least 7, at least 8, at least 9, or at least 10 carbon-carbon
double bonds, triple bonds, or any combination thereof. In another
example, the unsaturated fatty acids or residues thereof can
comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unsaturated bonds, where
any of the stated values can form an upper or lower endpoint when
appropriate.
[0053] Monoene Acids and Residues
[0054] In one aspect, the unsaturated fatty acids or residues
thereof can comprise one carbon-carbon double bond (i.e., a monoene
acid or residue). Examples of unsaturated fatty acids and residues
thereof that are suitable for the compounds and methods disclosed
herein include, but are not limited to, those in the following
Table 1.
TABLE-US-00001 TABLE 1 Examples of Monoene Acids and Residues Total
number of carbon Carbon number where double bond begins. atoms in
the fatty acid or ("c" denotes a cis double bond; residue chain.
"t" denotes a trans double bond) 10 4c 12 4c 14 4c 9c 16 3t 4c 5t
6c 6t 9c (palmitooleic) 11c 18 3t 5c 5t 6c (petroselinic) 6t 9c
(oleic) 10c 11c (cis-vaccenic) 11t (trans-vaccenic) 13c 20 5c 9c
(gadolenic) 11c 13c 15c 22 5c 11c (cetoleic) 13c (erucic) 15c 24
15c (selacholeic, nervonic) 26 9c 17c (ximenic) 28 9c 19c
(lumequic) 30 21c
[0055] Polyene Acids and Residues (Methylene Interrupted)
[0056] In another aspect, the unsaturated fatty acids and residues
thereof can comprise at least two unsaturated bonds (e.g., polyene
acids or residues). In some examples, the unsaturated fatty acids
and residues thereof can comprise at least one pair of methylene
interrupted unsaturated bonds. By "methylene interrupted
unsaturated bond" is meant that one carbon-carbon double or triple
bond is separated from another carbon-carbon double or triple bond
by at least one methylene group (i.e., CH.sub.2). Specific examples
of unsaturated fatty acids that contain at least one pair of
methylene interrupted unsaturated bonds include, but are not
limited to, the n-1 family derived from 9, 12, 15-16:3; n-2 family
derived from 9, 12, 15-17:3, 15:3, 17:3, 17:4, 20:4; n-3 family
derived from 9, 12, 15-18:3, 15:2, 15:3, 15:4, 16:3, 16:4, 18:3
(a-linolenic), 18:4, 18:5, 20:2, 20:3, 20:4; 20:5 (EPA), 21:5,
22:3, 22:5 (DPA), 22:6 (DHA), 24:3, 24:4, 24:5, 24:6, 26:5, 26:6,
28:7, 30:5; n-4 family derived from 9, 12-16:2, 16:2, 16:3, 18:2,
18:3; n-5 family derived from 9, 12-17:2, 15:2, 17:2, 17:3, 19:2,
19:4, 20:3, 20:4, 21:4, 21:5; n-6 family derived from 9, 12-18:2,
15:2, 16:2, 18:2 (linoleic acid), 18:3 (.gamma.-linolenic acid);
20:2, 20:3, 20:4 (arachidonic acid), 22:2, 22:3, 22:4 (adrenic
acid), 22:5, 24:2, 24:4, 25:2, 26:2, 30:4; n-7 family derived from
9-16:1, 15:2, 16:2, 17:2, 18:2, 19:2; n-8 family derived from
9-17:1, 15:2, 16:2, 17:2, 18:2, 19:2; n-9 family derived from
9-18:1, 17:2, 18:2, 20:2, 20:3, 22:3, 22:4; n-11 family 19:2, and
the n-12 family 20:2.
[0057] In the above paragraph, the compounds are identified
referring first to the "n-x family," where x is the position in the
fatty acid where the first double bond begins. The numbering scheme
begins at the terminal end of the fatty acid, where, for example,
the terminal CH.sub.3 group is designated position 1. In this
sense, the n-3 family would be an omega 3 fatty acid, as described
herein. The next number identifies the total number of carbon atoms
in the fatty acid. The third number, which is after the colon,
designates the total number of double bonds in the fatty acid. So,
for example, in the n-1 family, 16:3, refers to a 16 carbon long
fatty acid with 3 double bonds, each separated by a methylene,
wherein the first double bond begins at position 1, i.e., the
terminal end of the fatty acid. In another example, in the n-6
family, 18:3, refers to an 18 carbon long fatty acid with 3
methylene interrupted double bonds beginning at position 6, i.e.,
the sixth carbon from the terminal end of the fatty acid, and so
forth.
[0058] Some other examples of fatty acids and residues thereof are
those that contain at least one pair of unsaturated bonds
interrupted by more than one methylene group. Suitable examples of
these acids and residues thereof include, but are not limited to,
those in the following Table 2:
TABLE-US-00002 TABLE 2 Examples of Polyene Acids and Residues with
Double Bonds Interrupted by Several Methylene Units Total number of
carbon Carbon number where double bond begins. atoms in the fatty
acid or ("c" denotes a cis double bond; residue chain. "t" denotes
a trans double bond) 18 5, 9 5, 11 2t, 9, 12 3t, 9, 12 5t, 9, 12 5,
9, 12 5, 11, 14 3t, 9, 12, 15 5, 9, 12, 15 20 5, 11 5, 13 7, 11 7,
13 5, 11, 14 7, 11, 14 5, 11, 14, 17 22 5, 11 5, 13 7, 13 7, 15 7,
17 9, 13 9, 15
[0059] Polyene Acids and Residues (Conjugated)
[0060] Still other examples of unsaturated fatty acids and residues
thereof that are suitable for use in the compounds and methods
disclosed herein are those that contain at least one conjugated
unsaturated bond. By "conjugated unsaturated bond" is meant that at
least one pair of carbon-carbon double and/or triple bonds are
bonded together, without a methylene (CH.sub.2) group between them
(e.g., --CH.dbd.CH--CH.dbd.CH--). Specific examples of unsaturated
fatty acids that contain conjugated unsaturated bonds include, but
are not limited to, those in the following Table 3.
TABLE-US-00003 TABLE 3 Examples of Conjugated Polyene Acids and
Residues Total number of carbon Carbon number where double bond
begins. atoms in the fatty acid or ("c" denotes a cis double bond;
residue chain. "t" denotes a trans double bond) 10 2t, 4t, 6c 2c,
4t, 6t 3t, 5t, 7c 3c, 5t, 7t 12 3, 5, 7, 9, 11 14 3, 5, 7, 9, 11 18
10t, 12t 8c, 10t, 12c (jacaric) 8t, 10t, 12c (calendic) 8t, 10t,
12t 9t, 11t, 13c (catalpic) 9c, 11t, 13t (.alpha.-eleostearic) 9c,
11t, 13c (punicic) 9t, 11t, 13t (.beta.-eleostearic) 9c, 11t, 13t,
15c (.alpha.-parinaric) 9t, 11t, 13t, 15t (.beta.-parinaric)
[0061] Omega-3 Fatty Acids
[0062] Omega-3 fatty acids are certain unsaturated fatty acids that
are particularly useful in the compounds and methods disclosed
herein. Omega-3 fatty acids not only exhibit proven effects on
lowering serum triglyceride levels, but they have strong connection
to diabetes. For instance, docosahexaenoic acid (DHA) also has a
strong insulin permeability enhancement effect, and it is viewed as
a potential absorption enhancer for intestinal delivery of insulin
(Onuki, et al., Int J Pharm 198:147-56, 2000). DHA intake can
prevent certain biochemical processes that originate from insulin
deficiency (Ovide-Bordeaux and Grynberg, Am J Physiol Regul Integr
Comp Physiol 286:R519-27, 2003) and both DHA and EPA
(eicosapentaenoic acid) can significantly increase fasting insulin
levels (Mori, et al., Am J Clin Nutr 71:1085-94, 2000).
[0063] An omega-3 fatty acid is an unsaturated fatty acid that
contains as its terminus CH.sub.3--CH.sub.2--CH.dbd.CH--. Specific
examples of omega-3 fatty acids that are suitable for use herein
include, but are not limited to, linolenic acid (18:3.omega.3),
octadecatetraenoic acid (18:4.omega.3), eicosapentaenoic acid
(20:5.omega.3) (EPA), docosahexaenoic acid (22:6.omega.3) (DHA),
docosapentaenoic acid (22:6.omega.3) (DPA), derivatives thereof,
and combinations thereof.
[0064] In still other examples, the unsaturated fatty acids or
residues thereof can be derived from a compound comprising Formula
II:
##STR00004##
wherein R.sup.4 can be a C.sub.3-C.sub.40 alkyl or alkenyl group
comprising at least one double bond. In a further example, R.sup.4
can be a C.sub.5-C.sub.38, C.sub.6-C.sub.36, C.sub.8-C.sub.34,
C.sub.10-C.sub.32, C.sub.12-C.sub.30, C.sub.14-C.sub.28,
C.sub.16-C.sub.26, or C.sub.18-C.sub.24 alkenyl group. In yet
another example, the alkenyl group of R.sup.4 can have from 2 to 6,
from 3 to 6, from 4 to 6, or from 5 to 6 double bonds. Still
further, the alkenyl group of R.sup.4 can have from 1, 2, 3, 4, 5,
or 6 double bonds, where any of the stated values can form an upper
or lower endpoint when appropriate.
[0065] Exemplary Unsaturated Fatty Acids
[0066] Some examples of unsaturated fatty acids and residues
derived therefrom that can be used in the compounds and methods
disclosed herein include, but are not limited to, linoleic acid,
linolenic acid, .gamma.-linolenic acid, arachidonic acid, mead
acid, stearidonic acid, .alpha.-eleostearic acid, eleostearic acid,
pinolenic acid, docosadienic acid, docosatetraenoic acid,
docosapentaenoic acid, docosahexaenoic acid, octadecadienoic acid,
octadecatrienoic acid, eicosatetraenoic acid, eicosapentaenoic, or
any combination thereof. In one aspect, the unsaturated fatty acid
residue can be derived from eicosapentaenoic acid 20:5.omega.3
(EPA), docosahexaenoic acid 22:6.omega.3 (DHA), docosapentaenoic
acid 22:5.omega.3 (DPA), and any combination thereof.
[0067] Unsaturated with Triple Bonds
[0068] Additional examples of suitable unsaturated fatty acids and
residues thereof which are suitable in the disclosed compounds and
methods include, but are not limited to, allenic and acetylenic
acids, such as, C14: 2, 4, 5; C18: 5, 6 (laballenic); 5, 6, 16
(lamenallenic); C18: 6a (tarinic); 9a; 9a, 11t (ximenynic); 9a,
11a; 9a, 11a, 13c (bolekic); 9a, 11a, 13a, 15e, 8a, 10t (pyrulic)
9c, 12a (crepenynic); 9c, 12a, 14c (dehydrocrepenynic acid); 6a,
9c, 12c; 6a, 9c, 12c, 15c, 8a, 11c, 14c and corresponding
.DELTA.17e derivatives, 8-OH, derivatives and .DELTA.17e, 8-OH
derivatives.
[0069] Additional Fatty Acids
[0070] Branched-chain acids, particularly iso-acids and anteiso
acids, polymethyl branched acids, phytol based acids (e.g.,
phytanic, pristanic), furanoid acids are also suitable fatty acids,
including the residues derived therefrom, for use in the compounds
and methods disclosed herein.
[0071] Still further, suitable fatty acids and residues thereof
include, but are not limited to, cyclic acids, such as cyclopropane
fatty acids, cyclopropene acids (e.g., lactobacillic), sterulic,
malvalic, sterculynic, 2-hydroxysterculic, aleprolic, alepramic,
aleprestic, aleprylic alepric, hydnocarpic, chaulmoogric hormelic,
manaoic, gorlic, oncobic, cyclopentenyl acids, cyclohexylalkanoic
acids, and any combination thereof.
[0072] Hydroxy acids, such as butolic, ricinoleic, isoricinoleic,
densipolic, lesquerolic, and auriolic, are also suitable fatty
acids that can be used in the compounds and methods disclosed
herein.
[0073] Epoxy acids, such as epoxidated C18:1 and C18:2, and
furanoid acids, are further examples of fatty acids that can be
used in the disclosed compounds and methods.
[0074] Permutations of R.sup.1 and R.sup.2
[0075] In one aspect, the disclosed compounds comprising Formula I
can have R.sup.1 being any of the unsaturated fatty acid residues
disclosed above. Further, in another aspect, the disclosed
compounds can have R.sup.1 being any of the unsaturated fatty acid
residues disclosed above and R.sup.2 can be H. In yet another
aspect, the disclosed compounds can have R.sup.1 and R.sup.2 each
being any of the unsaturated fatty acid residues disclosed above.
For example, R.sup.1 and R.sup.2 can be the same unsaturated fatty
acid residue or, in another example, R.sup.1 and R.sup.2 can be
different unsaturated fatty acid residues. In a further aspect,
R.sup.1 can be any of the unsaturated fatty acid residues disclosed
above and R.sup.2 can be any of the saturated fatty acid residues
disclosed above.
[0076] In some particular examples, R.sup.1 and R.sup.2 can be
unsaturated fatty acid residues derived from fish oil. In other
examples, R.sup.1 and R.sup.2 can be unsaturated fatty acid
residues comprising at least 20 carbon atoms. In yet other
examples, R.sup.1 and R.sup.2 can be unsaturated fatty acid
residues comprising at least one pair of methylene interrupted
unsaturated bonds. In still other examples, R.sup.1 and R.sup.2 can
be unsaturated fatty acid residues derived from an omega-3 fatty
acid.
[0077] In other specific examples of the disclosed compounds,
R.sup.1 and R.sup.2 can be unsaturated fatty acid residues derived
from a compound comprising Formula II:
##STR00005##
wherein R.sup.4 can a C.sub.3-C.sub.40 alkyl or alkenyl group
comprising at least one double bond. In one example, R.sup.4 can be
from 2 to 6 double bonds.
[0078] In other specific examples, R.sup.1 and R.sup.2 can be
unsaturated fatty acid residues derived from linoleic acid,
linolenic acid, gamma-linolenic acid, arachidonic acid, mead acid,
stearidonic acid, alpha-eleostearic acid, eleostearic acid,
pinolenic acid, docosadienic acid, docosatetraenoic acid,
octadecadienoic acid, octadecatrienoic acid, eicosatetraenoic acid,
or any combination thereof. In further examples, R.sup.1 and
R.sup.2 can be unsaturated fatty acid residues derived from
eicosapentaenoic acid 20:5.omega.3 (EPA), docosahexaenoic acid
22:6.omega.3 (DHA), docosapentaenoic acid 22:5.omega.3 (DPA), or
any combination thereof.
[0079] In one aspect, the disclosed compounds comprising Formula I
can have substituents OR.sup.1 and OR.sup.2 in the ortho-, meta-,
or para-positions.
[0080] R.sup.3
[0081] In one aspect, the disclosed compounds comprising Formula I
can have R.sup.3 being, independently, H, OH, alkyl, alkoxide,
alkenyl, or alkynyl, as described above. For example, at least one
R.sup.3 substituent can be a methyl, ethyl, or propyl. In another
example, at least one R.sup.3 substituent can be a methoxide,
ethoxide, or propoxide. In yet another example, at least one
R.sup.3 substituent can be a alkenyl group having the formula
--[CH.sub.2CH.dbd.C(CH.sub.3)CH.sub.2--].sub.n--H, where n is an
integer of from 1 to 12. In still another example, one R.sup.3
substituent in Formula I can be
--[CH.sub.2CH.dbd.C(CH.sub.3)CH.sub.2--].sub.n--H, where n is an
integer of from 1 to 12, one R.sup.3 substituent can be methyl, and
two R.sup.3 substituents can be methoxy.
[0082] Exemplary Compounds
[0083] Some additional examples of compounds disclosed and
described herein can include, but are not limited to, compounds
comprising the following Formula IV:
##STR00006##
wherein, as described above for Formula I, R.sup.1 is an
unsaturated fatty acid residue, R.sup.2 is H or a fatty acid
residue, and R.sup.3 and each R.sup.6 is an alkyl group and n is
from 1 to 12.
[0084] It should be understood that in Formula IV substituents
R.sup.1 and R.sup.2 can be interchangeable. That is, Formula IV can
also be written as shown:
##STR00007##
[0085] In Formula IV, the unsaturated fatty acid residues of
R.sup.1 and fatty acid residues (saturated or unsaturated) of
R.sup.2 can be any fatty acid as described herein. In one example,
R.sup.1 can be any unsaturated fatty acid residue as described
herein. In another example, R.sup.1 and R.sup.2 can be any
unsaturated fatty acid residue as described herein. In yet another
example, either R.sup.1 or R.sup.2 or both R.sup.1 and R.sup.2 can
be derived from fish oil. In another example, either R.sup.1 or
R.sup.2 or both R.sup.1 and R.sup.2 can comprise at least 20 carbon
atoms. In still another example, either R.sup.1 or R.sup.2 or both
R.sup.1 and R.sup.2 can be an unsaturated fatty acid residue
comprising at least one pair of methylene interrupted unsaturated
bonds.
[0086] In one aspect, either R.sup.1 or R.sup.2 or both R.sup.1 and
R.sup.2 can be derived from an omega-3 fatty acid. For example,
either R.sup.1 or R.sup.2 or both R.sup.1 and R.sup.2 can be
unsaturated fatty acid residues derived from a compound comprising
Formula II:
##STR00008##
wherein R.sup.4 can be a C.sub.3-C.sub.40 alkyl or alkenyl group
comprising at least one double bond. R.sup.4 can have from, for
example, 2 to 6 double bonds or from 3 to 5 double bonds. In yet
another example, either R.sup.1 or R.sup.2 or both R.sup.1 and
R.sup.2 can be derived from linoleic acid, linolenic acid,
gamma-linolenic acid, arachidonic acid, mead acid, stearidonic
acid, alpha-eleostearic acid, eleostearic acid, pinolenic acid,
docosadienic acid, docosatetraenoic acid, octadecadienoic acid,
octadecatrienoic acid, eicosatetraenoic acid, or any combination
thereof. In still another example, either R.sup.1 or R.sup.2 or
both R.sup.1 and R.sup.2 can be derived from eicosapentaenoic acid
20:5.omega.3 (EPA), docosahexaenoic acid 22:6.omega.3 (DHA),
docosapentaenoic acid 22:5.omega.3 (DPA), or any combination
thereof.
[0087] In one particular aspect, disclosed herein is a compound,
comprising Formula I:
##STR00009##
wherein R.sup.1 is a fatty acid residue, R.sup.2 is, independently,
a H or a fatty acid residue; and R.sup.3 is, independently, H, OH,
alkyl, alkoxyl, alkenyl, or alkynyl, and wherein the compound is
not Formula V
##STR00010##
wherein R.sup.5 is a linear or branched alkyl group with 1 to 20
carbon atoms, or an aryl group, optionally substituted with alkyl
from 1 to 6 carbon atoms and X is absent or a CO group.
[0088] Additional Properties
[0089] The disclosed compounds can be, in one aspect, bioavailable.
"Bioavailable" means that a compound is in a form that allows for
it, or a portion of the amount administered, to be absorbed by,
incorporated into, or otherwise physiologically available to a
subject or patient to whom it is administered.
[0090] Further, chemical coupling benzenediol derivatives with
fatty acids, as disclosed herein, can yield syrup-like compounds
that are more palatable than a corresponding heterogeneous
solid/liquid mixture.
Methods of Making
[0091] Also disclosed herein are methods for preparing the
disclosed compounds. In one aspect, the compounds disclosed can be
prepared by reacting a compound comprising Formula III:
##STR00011##
wherein R.sup.3 is, independently, H, OH, alkyl, alkoxyl, alkenyl,
or alkynyl with one or more unsaturated fatty acids or a derivative
thereof.
[0092] In one aspect, the compound represented by Formula III can
have can have the substituents OH in the para-, meta-, or
ortho-positions (e.g., derivatives of hydroquinone
(1,4-benzenediol), resorcinol (1,3-benzenediol), and catechol
(1,2-benzenediol), respectively.
[0093] In another aspect, of the compounds represented by Formula
III, R.sup.3 can be, independently, H, OH, alkyl, alkoxide,
alkenyl, or alkynyl, as defined above. For example, at least one
R.sup.3 substituent can be a methyl, ethyl, or propyl. In another
example, at least one R.sup.3 substituent can be a methoxide,
ethoxide, or propoxide. In yet another example, at least one
R.sup.3 substituent can be a alkenyl group having the formula
--[CH.sub.2CH.dbd.C(CH.sub.3)CH.sub.2--].sub.n--H, where n is an
integer of from 1 to 12. In still another example, one R.sup.3
substituent in Formula III can be
--[CH.sub.2CH.dbd.C(CH.sub.3)CH.sub.2--].sub.n--H, where n is an
integer of from 1 to 12, one R.sup.3 substituent can be methyl, and
two R.sup.3 substituents can be methoxy.
[0094] In one specific example, the compound represented by Formula
III can comprise Formula VI:
##STR00012##
wherein R.sup.3 and each R.sup.6 can be an alkyl group and n can be
from 1 to 12, for example, the compound represented by Formula VI
can be CoQ.sub.1-12. In one specific example, R.sup.3 and each
R.sup.6 can be methyl and n is 10. This compound is the reduced
form of CoQ.sub.10, which is referred to herein as CoQ.sub.10red.
CoQ.sub.10red can be produced from CoQ.sub.10 by reacting
CoQ.sub.10 with a reducing agent such as, for example, NaBH.sub.4
or hydrogenation with Zn and AcOH. Various techniques are described
herein for producing CoQ.sub.10red.
[0095] Unsaturated Fatty Acids
[0096] In one aspect, the compound comprising Formula III or
Formula VI can be reacted with any unsaturated fatty acid or
derivative thereof as disclosed herein. By "derivative thereof" is
meant that the protonated or unprotonated unsaturated fatty acid,
its salt, its ester (e.g., methyl, ethyl, phenyl, benzyl, etc.),
its thioester, its amide, its acid halide (e.g., acid chloride or
bromide), or its anhydride (e.g., mixed anhydride) can be used
herein. Such derivatives of the fatty acids described above are
considered as being disclosed herein. In one example, the
unsaturated fatty acid or derivative thereof can be derived from
fish oil. In another example, the unsaturated fatty acid or
derivative thereof can comprise at least 20 carbon atoms. In yet
another example, the unsaturated fatty acid or derivative thereof
can comprise at least one pair of methylene interrupted unsaturated
bonds. In a further example, the unsaturated fatty acid or
derivative thereof can be an omega-3 fatty acid. In still another
example, the unsaturated fatty acid or derivative thereof can
comprise the Formula II:
##STR00013##
wherein R.sup.4 can be a C.sub.3-C.sub.40 alkyl or alkenyl group
comprising at least one double bond. The substituent R.sup.4 can
have from 2 to 6 double bonds.
[0097] In some specific examples, the compound comprising Formula
III or Formula VI can be reacted with an unsaturated fatty acid or
derivative thereof derived from linoleic acid, linolenic acid,
gamma-linolenic acid, arachidonic acid, mead acid, stearidonic
acid, alpha-eleostearic acid, eleostearic acid, pinolenic acid,
docosadienic acid, docosatetraenoic acid, octadecadienoic acid,
octadecatrienoic acid, eicosatetraenoic acid, or any combination
thereof. In other specific examples, the unsaturated fatty acid or
derivative thereof can comprise eicosapentaenoic acid 20:5.omega.3
(EPA), docosahexaenoic acid 22:6.omega.3 (DHA), docosapentaenoic
acid 22:5.omega.3 (DPA), or any combination thereof.
[0098] In one particular aspect, the compound represented by
Formula VI, wherein R.sup.3 and each R.sup.6 is a methyl group and
n is 10 is reacted with an unsaturated fatty acid or derivative
thereof derived from fish oil.
[0099] Concentration
[0100] In the methods disclosed herein, the reaction with the
compounds represented by Formula III or VI and one or more
unsaturated fatty acid or derivatives thereof can take place under
various conditions. For example, the reaction can take place neat.
In another aspect, the reaction can take place in any solvent. For
example, the reaction can take place in an aqueous solvent, such
as, but not limited to, water, aqueous hexane, aqueous ethanol,
aqueous methanol, aqueous propanol, and the like. The reaction can
also take place in non-aqueous solvents, such as, but not limited
to, DMSO, DMF, THF, benzene, toluene, hexane, pentane,
dichloromethane, acetone, pyridine, and the like. In another
example, the reaction can take place in a diphasic system
containing an aqueous phase and an organic phase. In these systems,
suitable organic phases can contain, for example, butanol, pentane,
cyclopentane, hexane, cyclohexane, heptane, benzene, toluene,
carbon tetrachloride, chloroform, methylene chloride,
dichloroethane, ethyl acetate, ether, MEK, octane, diisopropyl
ether, tri and tetrachlorethane, and the like. The amount of
solvent used and the concentration of the compound of Formula III
or VI and/or unsaturated fatty acid or derivative thereof will
depend on the particular compound being prepared, the type of
benzenediol derivative of Formula III or VI, the type of
unsaturated fatty acid or derivative thereof, the type of solvent,
preference, and the like.
[0101] Temperature
[0102] The compound of Formula III or VI can be reacted with the
unsaturated fatty acid or derivative thereof at any temperature
sufficient to form a bond between one or more hydroxyl substituents
on the aromatic ring and the unsaturated fatty acid or derivative
thereof. Typically, the reaction can take place at an elevated
temperature. The precise elevated temperature can depend on the
particular fatty acid being used, the particular benzenediol
derivative of Formula III or VI being used, the solvent, the amount
or concentration of the reagents, preference, and the like.
Suitable temperatures at which the benzenediol derivative of
Formula III or VI can be reacted with the fatty acid include, but
are not limited to, from about 20 to about 200.degree. C., from
about 50 to about 220.degree. C., from about 70 to about
240.degree. C., from about 90 to about 260.degree. C., or from
about 110 to about 280.degree. C. In other examples, the
temperature of the reaction can be at about 20, 25, 30, 35, 40, 45,
50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120,
125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185,
190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250,
255, 260, 265, 270, 275, 280, 285, 290, or 300.degree. C., where
any of the stated values can form an upper or lower endpoint when
appropriate.
[0103] Specific Examples
[0104] In one example, Scheme 1 illustrates the direct acylation of
the reduced form of CoQ.sub.10 (i.e., Formula VI with R.sup.3 and
each R.sup.6 being methyl and n=10, with a DHA derivative, where X
is a leaving group. Coenzyme Q.sub.10 (CoQ.sub.10) is available
generically from numerous manufacturers. Branded products include
Lynae CoQ.sub.10 (Boscogen, Irvine Calif.), Natures Blend Coenzyme
Q.sub.10 (National Vitamin Company, Porterville, Calif.) and Ultra
CoQ.sub.10 (Twinlab, Hauppauge, N.Y.).
[0105] The scheme is written only for acylation of one of the two
hydroxy groups but it is contemplated that either or both groups
can be acylated and the ratio would depend on the reaction
conditions.
##STR00014##
[0106] Also, disclosed herein are compounds prepared by the methods
disclosed herein.
Supplements
[0107] Also disclosed herein are nutritional supplements. A
nutritional supplement is any compound or composition that can be
administered to or taken by a subject to provide, supply, or
increase a nutrient(s) (e.g., vitamin, mineral, essential trace
element, amino acid, peptide, nucleic acid, oligonucleotide, lipid,
cholesterol, steroid, carbohydrate, and the like). In one aspect,
disclosed herein are nutritional supplements comprising any of the
compounds disclosed herein. For example, a nutritional supplement
can comprise any compound comprising Formula I or IV. The fatty
acid residues of these formulas can be any fatty acid as disclosed
herein (e.g., unsaturated or saturated fatty acid residues).
[0108] The nutritional supplement can comprise any amount of the
compounds disclosed herein, but will typically contain an amount
determined to supply a subject with a desired dose of a benzenediol
derivative (e.g., CoQ.sub.10) and/or fatty acids. The exact amount
of compound required in the nutritional supplement will vary from
subject to subject, depending on the species, age, weight and
general condition of the subject, the severity of the dietary
deficiency being treated, the particular mode of administration,
and the like. Thus, it is not possible to specify an exact amount
for every nutritional supplement. However, an appropriate amount
can be determined by one of ordinary skill in the art using only
routine experimentation given the teachings herein. In one specific
example, a nutritional supplement can comprise from about 0.05 to
about 20%, from about 1 to about 7.5%, or from about 3 to about 5%
by weight of the compound. In another example, the nutritional
supplement can comprise from about 0.05, 0.10, 0.15, 0.20, 0.25,
0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80,
0.85, 0.90, 0.95, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5,
6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 10.5, 11.0, 11.5, 12.0,
12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5,
18.0, 18.5, 19.0, 19.5, or 20.0% by weight of the compound, where
any of the stated values can form an upper or lower endpoint when
appropriate. In another aspect, when the nutritional supplement,
the supplement can be composed of up to 100% of the supplement.
[0109] The nutritional supplement can also comprise other
nutrient(s) such as vitamins trace elements, minerals, and the
like. Further, the nutritional supplement can comprise other
components such as preservatives, antimicrobials, anti-oxidants,
chelating agents, thickeners, flavorings, diluents, emulsifiers,
dispersing aids, and/or binders.
[0110] The nutritional supplements are generally taken orally and
can be in any form suitable for oral administration. For example, a
nutritional supplement can typically be in a tablet, gel-cap,
capsule, liquid, sachets, or syrup form.
Pharmaceutical Formulation
[0111] Also, disclosed herein are pharmaceutical formulations. In
one aspect, a pharmaceutical formulation can comprise any of the
compounds disclosed herein with a pharmaceutically acceptable
carrier. For example, a pharmaceutical formulation can comprise a
compound comprising Formula I or IV and a pharmaceutically
acceptable carrier. The disclosed pharmaceutical formulations can
be used therapeutically or prophylactically.
[0112] By "pharmaceutically acceptable" is meant a material that is
not biologically or otherwise undesirable, i.e., the material may
be administered to a subject without causing any undesirable
biological effects or interacting in a deleterious manner with any
of the other components of the pharmaceutical formulation in which
it is contained. The carrier would naturally be selected to
minimize any degradation of the active ingredient and to minimize
any adverse side effects in the subject, as would be well known to
one of skill in the art.
[0113] Pharmaceutical carriers are known to those skilled in the
art. These most typically would be standard carriers for
administration of drugs to humans, including solutions such as
sterile water, saline, and buffered solutions at physiological pH.
Suitable carriers and their formulations are described in
Remington: The Science and Practice of Pharmacy (19th ed.) Gennaro,
ed., Mack Publishing Company, Easton, Pa., 1995, which is
incorporated by reference herein for its teachings of carriers and
pharmaceutical formulations. Typically, an appropriate amount of a
pharmaceutically-acceptable salt is used in the formulation to
render the formulation isotonic. Examples of the
pharmaceutically-acceptable carrier include, but are not limited
to, saline, Ringer's solution and dextrose solution. The pH of the
solution is preferably from about 5 to about 8, and more preferably
from about 7 to about 7.5. Further carriers include sustained
release preparations such as semipermeable matrices of solid
hydrophobic polymers containing the disclosed compounds, which
matrices are in the form of shaped articles, e.g., films,
liposomes, microparticles, or microcapsules. It will be apparent to
those persons skilled in the art that certain carriers can be more
preferable depending upon, for instance, the route of
administration and concentration of composition being administered.
Other compounds can be administered according to standard
procedures used by those skilled in the art.
[0114] Pharmaceutical formulations can include additional carriers,
as well as thickeners, diluents, buffers, preservatives, surface
active agents and the like in addition to the compounds disclosed
herein. Pharmaceutical formulations can also include one or more
additional active ingredients such as antimicrobial agents,
antiinflammatory agents, anesthetics, and the like.
[0115] The pharmaceutical formulation can be administered in a
number of ways depending on whether local or systemic treatment is
desired, and on the area to be treated. Administration may be
topically (including ophthalmically, vaginally, rectally,
intranasally), orally, by inhalation, or parenterally, for example
by intravenous drip, subcutaneous, intraperitoneal or intramuscular
injection. The disclosed compounds can be administered orally,
intravenously, intraperitoneally, intramuscularly, subcutaneously,
intracavity, or transdermally.
[0116] Pharmaceutical formulations for oral administration include,
but are not limited to, powders or granules, suspensions or
solutions in water or non-aqueous media, capsules, sachets, or
tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing
aids, anti-oxidants, or binders may be desirable.
[0117] Pharmaceutical formulations for parenteral administration
include sterile aqueous or non-aqueous solutions, suspensions, and
emulsions. Examples of non-aqueous solvents are propylene glycol,
polyethylene glycol, vegetable oils such as olive oil, fish oils,
and injectable organic esters such as ethyl oleate. Aqueous
carriers include water, alcoholic/aqueous solutions, emulsions or
suspensions, including saline and buffered media. Parenteral
vehicles include sodium chloride solution, Ringer's dextrose,
dextrose and sodium chloride, lactated Ringer's, or fixed oils.
Intravenous vehicles include fluid and nutrient replenishers,
electrolyte replenishers (such as those based on Ringer's
dextrose), and the like. Preservatives and other additives may also
be present such as, for example, antimicrobials, anti-oxidants,
chelating agents, and inert gases and the like.
[0118] Pharmaceutical formulations for topical administration may
include ointments, lotions, creams, gels, drops, suppositories,
sprays, liquids and powders. Conventional pharmaceutical carriers,
aqueous, powder or oily bases, thickeners and the like may be
necessary or desirable.
[0119] Some of the formulations can potentially be administered as
a pharmaceutically acceptable acid- or base-addition salt, formed
by reaction with inorganic acids such as hydrochloric acid,
hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid,
sulfuric acid, and phosphoric acid, and organic acids such as
formic acid, acetic acid, propionic acid, glycolic acid, lactic
acid, pyruvic acid, oxalic acid, malonic acid, succinic acid,
maleic acid, and fumaric acid, or by reaction with an inorganic
base such as sodium hydroxide, ammonium hydroxide, potassium
hydroxide, and organic bases such as mono-, di-, trialkyl and aryl
amines and substituted ethanolamines.
Delivery Devices
[0120] Any of the compounds described herein can be incorporated
into a delivery device. Examples of delivery devices include, but
are not limited to, microcapsules, microspheres, nano spheres or
nanoparticles, liposomes, noisome, nanoerythrosome, solid-liquid
nanoparticles, gels, gel capsules, tablets, lotions, creams,
sprays, emulsions, Other examples of delivery devices that are
suitable for non-oral administration include pulmospheres. Examples
of particular delivery devices useful herein are described
below.
[0121] The disclosed compounds can be incorporated into liposomes.
As is known in the art, liposomes are generally derived from
phospholipids or other lipid substances. Liposomes are formed by
mono- or multi-lamellar hydrated liquid crystals that are dispersed
in an aqueous medium. Any non-toxic, physiologically acceptable and
metabolizable lipid capable of forming liposomes can be used. The
disclosed compositions in liposome form can contain, in addition to
a compound disclosed herein, stabilizers, preservatives,
excipients, and the like. Examples of suitable lipids are the
phospholipids and the phosphatidyl cholines (lecithins), both
natural and synthetic. Methods of forming liposomes are known in
the art. See, e.g., Prescott, Ed., Methods in Cell Biology, Volume
XIV, Academic Press, New York, p. 33 et seq., 1976, which is hereby
incorporated by reference herein for its teachings of liposomes and
their preparation.
[0122] In other examples, the liposomes can be cationic liposomes
(e.g., DOTMA, DOPE, DC cholesterol) or anionic liposomes. Liposomes
can further comprise proteins to facilitate targeting a particular
cell, if desired. Administration of a composition comprising a
compound and a cationic liposome can be administered to the blood
afferent to a target organ or inhaled into the respiratory tract to
target cells of the respiratory tract. Regarding liposomes, see
e.g., Brigham, et al., Am J Resp Cell Mol Biol 1:95-100, 1989;
Felgner, et al., Proc Natl Acad Sci USA 84:7413-7, 1987; and U.S.
Pat. No. 4,897,355, which are incorporated by reference herein for
their teachings of liposomes. As one example, delivery can be via a
liposome using commercially available liposome preparations such as
LIPOFECTIN, LIPOFECTAMINE (GIBCO-BRL, Inc., Gaithersburg, Md.),
SUPERFECT (Qiagen, Inc. Hilden, Germany) and TRANSFECTAM (Promega
Biotec, Inc., Madison, Wis.), as well as other liposomes developed
according to procedures standard in the art. Liposomes where the
diffusion of the compound or delivery of the compound from the
liposome is designed for a specific rate or dosage can also be
used.
[0123] As described herein, niosomes are delivery devices that can
be used to deliver the compositions disclosed herein. Noisomes are
multilamellar or unilamellar vesicles involving non-ionic
surfactants. An aqueous solution of solute is enclosed by a bilayer
resulting from the organization of surfactant macromolecules.
Similar to liposomes, noisomes are used in targeted delivery of,
for example, anticancer drugs, including methotrexate, doxorubicin,
and immunoadjuvants. They are generally understood to be different
from transferosomes, vesicles prepared from amphiphilic
carbohydrate and amino group containing polymers, e.g.,
chitosan.
[0124] As described herein, nanoerythrosomes are delivery devices
that can be used to deliver the compositions disclosed herein.
Nanoerythrosomes are nano-vesicles made of red blood cells via
dialysis through filters of defined pore size. These vesicles can
be loaded with a diverse array of biologically active molecules,
including proteins and the compositions disclosed herein. They
generally serve as ideal carriers for antineoplastic agents like
bleomycin, actinomycin D, but can be used for steroids, other
lipids, etc.
[0125] Artificial red blood cells, as described herein, are further
delivery devices that can be used to deliver the compositions
disclosed herein. Artificial red blood cells can be generated by
interfacial polymerization and complex emulsion methods. Generally,
the "cell" wall is made of polyphtaloyl L-lysine
polymer/polystyrene and the core is made of a hemoglobin solution
from sheep hemolysate. Hemoglobin loaded microspheres typically
have particle sizes of from about 1 to about 10 mm. Their size,
flexibility, and oxygen carrying capacity is similar to red blood
cells.
[0126] Solid-lipid nanoparticles, as described herein, are other
delivery devices that can be used to deliver the compositions
disclosed herein. Solid-lipid nanoparticles are nanoparticles,
which are dispersed in an aqueous surfactant solution. They are
comprised of a solid hydrophobic core having a monolayer of a
phospholipid coating and are usually prepared by high-pressure
homogenization techniques. Immunuomodulating complexes (ISCOMS) are
examples of solid-lipid nanoparticles. They are cage-like 40 nm
supramolecular assemblies comprising of phospholipid, cholesterol,
and hydrophobic antigens and are used mostly as immunoadjuvants.
For instance, ISCOMs are used to prolong blood-plasma levels of
subcutaneously injected cyclosporine.
[0127] Microspheres and micro-capsules, as described herein, are
yet other delivery devices that can be used to deliver the
compositions disclosed herein. In contrast to liposomal delivery
systems, microspheres and micro-capsules typically do not have an
aqueous core but a solid polymer matrix or membrane. These delivery
devices are obtained by controlled precipitation of polymers,
chemical cross-linking of soluble polymers, and interfacial
polymerization of two monomers or high-pressure homogenization
techniques. The encapsulated compound is gradually released from
the depot by erosion or diffusion from the particles. Successful
formulations of short acting peptides, such as LHRH agonists like
leuprorelin and triptoreline, have been developed. Poly(lactide
co-glycolide (PLGA) microspheres are currently used as monthly and
three monthly dosage forms in the treatment of advanced prostrate
cancer, endometriosis, and other hormone responsive conditions.
Leuprolide, an LHRH superagonist, was incorporated into a variety
of PLGA matrices using a solvent extraction/evaporation method. As
noted, all of these delivery devices can be used in the methods
disclosed herein.
[0128] Pulmospheres are still other examples of delivery devices
that can be used herein. Pulmospheres are hollow porous particles
with a low density (less than about 0.1 gm/mL). Pulmospheres
typically have excellent re-dispersibility and are usually prepared
by supercritical fluid condensation technology. Co-spray-drying
with certain matrices, such as carbohydrates, human serum albumin,
etc., can improve the stability of proteins and peptides (e.g.,
insulin) and other biomolecules for pulmonary delivery. This type
of delivery could be also accomplished with micro-emulsions and
lipid emulsions, which are ultra fine, thin, transparent
oil-in-water (o/w) emulsions formed spontaneously with no
significant input of mechanical energy. In this technique, an
emulsion can be prepared at a temperature, which must be higher
than the phase inversion temperature of the system. At elevated
temperature the emulsion is of water-in-oil (w/o) type and as it
cools at the phase inversion temperature, this emulsion is inverted
to become o/w. Due to their very small inner phase, they are
extremely stable and used for sustained release of steroids and
vaccines. Lipid emulsions comprise a neutral lipid core (i.e.,
triglycerides) stabilized by a monolayer of amphiphilic lipid
(i.e., phospholipid) using surfactants like egg lecithin
triglycerides and miglyol. They are suitable for passive and active
targeting.
[0129] There are other oral delivery systems under investigation
that are based on osmotic pressure modulation, pH modulation,
swelling modulation, altered density and floating systems,
mucoadhesiveness etc. These formulations and time-delayed
formulations to deliver drugs in accordance with circadian rhythm
of disease that are currently in use or investigation can be
applied for delivery of the compositions disclosed herein.
[0130] In one particular aspect disclosed herein, the disclosed
compounds, including nutritional supplement and pharmaceutical
formulations thereof, can be incorporated into microcapsules as
described herein.
[0131] In one aspect disclosed herein, the disclosed compounds can
be incorporated into microcapsules. In one aspect, the microcapsule
comprises an agglomeration of primary microcapsules and the
chromium compounds described herein, each individual primary
microcapsule having a primary shell, wherein the chromium compound
is encapsulated by the primary shell, wherein the agglomeration is
encapsulated by an outer shell. These microcapsules are referred to
herein as "multicore microcapsules." In another aspect, described
herein are microcapsules comprising a chromium compound, a primary
shell, and a secondary shell, wherein the primary shell
encapsulates the chromium compound, and the secondary shell
encapsulates the loading substance and primary shell. These
microcapsules are referred to herein as "single-core
microcapsules.
[0132] Optionally, other loading substances can be encapsulated
with the chromium compound. The loading substance can be any
substance that is not entirely soluble in the aqueous mixture. In
one aspect, the loading substance is a solid, a hydrophobic liquid,
or a mixture of a solid and a hydrophobic liquid. In another
aspect, the loading substance comprises a grease, an oil, a lipid,
a drug (e.g., small molecule), a biologically active substance, a
nutritional supplement (e.g., vitamins), a flavour compound, or a
mixture thereof. Examples of oils include, but are not limited to,
animal oils (e.g., fish oil, marine mammal oil, etc.), vegetable
oils (e.g., canola or rapeseed), mineral oils, derivatives thereof
or mixtures thereof. The loading substance can be a purified or
partially purified oily substance such as a fatty acid, a
triglyceride or ester thereof, or a mixture thereof. In another
aspect, the loading substance can be a carotenoid (e.g., lycopene),
a satiety agent, a flavor compound, a drug (e.g., a water insoluble
drug), a particulate, an agricultural chemical (e.g., herbicides,
insecticides, fertilizers), or an aquaculture ingredient (e.g.,
feed, pigment).
[0133] In one aspect, the loading substance can be an omega-3 fatty
acid. Examples of omega-3 fatty acids include, but are not limited
to, .alpha.-linolenic acid (18:3.omega.3), octadecatetraenoic acid
(18:4.omega.3), eicosapentaenoic acid (20:5.omega.3) (EPA),
docosahexaenoic acid (22:6.omega.3) (DHA), docosapentaenoic acid
(22:5.omega.3) (DPA), eicosatetraenoic acid (20:4.omega.3),
uncosapentaenoic acid (21:5.omega.3), docosapentaenoic acid
(22:5.omega.3) and derivatives thereof and mixtures thereof. Many
types of derivatives of omega-3 fatty acids are well known in the
art. Examples of suitable derivatives include, but are not limited
to, esters, such as phytosterol esters, branched or unbranched
C.sub.1-C.sub.30 alkyl esters, branched or unbranched
C.sub.2-C.sub.30 alkenyl esters, or branched or unbranched
C.sub.3-C.sub.30 cycloalkyl esters such as phytosterol esters and
C.sub.1-C.sub.6 alkyl esters. Sources of oils can be derived from
aquatic organisms (e.g., anchovies, capelin, Atlantic cod, Atlantic
herring, Atlantic mackerel, Atlantic menhaden, salmonids, sardines,
shark, tuna, etc) and plants (e.g., flax, vegetables, etc) and
microorganisms (e.g., fungi and algae).
[0134] In one aspect, the loading substance can contain an
antioxidant. Examples of antioxidants include, but are not limited
to, vitamin E, CoQ.sub.10, tocopherols, lipid soluble derivatives
of more polar antioxidants such as ascorbyl fatty acid esters
(e.g., ascorbyl palmitate), plant extracts (e.g., rosemary, sage
and oregano oils), algal extracts, and synthetic antioxidants
(e.g., BHT, TBHQ, ethoxyquin, alkyl gallates, hydroquinones,
tocotrienols).
[0135] A number of different polymers can be used to produce the
shell layers of the single and multicore microcapsules. Examples of
such polymers include, but are not limited to, a protein, a
polyphosphate, a polysaccharide, or a mixture thereof. In another
aspect, the shell material used to prepare the single- and
multicore microcapsules further comprises In another aspect, the
shell material used to prepare the single- and multicore
microcapsules further comprises gelatin type A, gelatin type B,
polyphosphate, gum arabic, alginate, chitosan, carrageenan, pectin,
starch, modified starch, alfa-lactalbumin, beta-lactoglobumin,
ovalbumin, polysorbiton, maltodextrins, cyclodextrins, cellulose,
methyl cellulose, ethyl cellulose, hydropropylmethylcellulose,
carboxymethylcellulose, milk protein, whey protein, soy protein,
canola protein, albumin, chitin, polylactides,
poly-lactide-co-glycolides, derivatized chitin, chitosan,
poly-lysine, various inorganic-organic composites, or any mixture
thereof. It is also contemplated that derivatives of these polymers
can be used as well. In another aspect, the polymer can be kosher
gelatin, non-kosher gelatin, Halal gelatin, or non-Halal
gelatin.
[0136] In one aspect, one or more of the shell layers in the single
and multicore microcapsules comprises gelatin having a Bloom number
less than 50. This gelatin is referred to herein as "low Bloom
gelatin." The Bloom number describes the gel strength formed at
10.degree. C. with a 6.67% solution gelled for 18 hours. In one
aspect, the low Bloom gelatin has a Bloom number less than 40, less
than 30, less than 20, or less than 10. In another aspect, the
gelatin has a Bloom number of 45, 40, 35, 30, 25, 20, 15, 10, 9, 8,
7, 6, 5, 4, 3, 2, 1, or 0, where any two values can be used to
produce a range. In another aspect, the low Bloom gelatin is in
both the primary shell and the outer shell of the multicore
microcapsule. In one aspect, the low Bloom gelatin is gelatin type
A. In another aspect, the low Bloom gelatin is gelatin type A
produced by Kenney & Ross Ltd., R.R. #3 Shelburne, NS Canada.
In another aspect, gelatin having a Bloom number of zero is in both
the primary shell and the outer shell of the multicore
microcapsule.
[0137] In one aspect, the material used to make the shells of the
single- or multicore microcapsules is a two-component system made
from a mixture of two different types of polymers. In one aspect,
the material is a complex coacervate between the polymer
components. Complex coacervation is caused by the interaction
between two oppositely charged polymers. In one aspect, the shell
material used to produce the single and multicore microcapsules is
composed of (1) low Bloom gelatin and (2) gelatin type B,
polyphosphate, gum arabic, alginate, chitosan, carrageenan, pectin,
carboxymethylcellulose, whey protein, soy protein, canola protein,
albumin, or a mixture thereof. The molar ratio of the different
polymers can vary. For example, the molar ratio of low Bloom
gelatin to the other polymer component is from 1:5 to 15:1. For
example, when low Bloom gelatin and polyphosphate are used, the
molar ratio of low Bloom gelatin to polyphosphate is about 8:1 to
about 12:1; when low Bloom gelatin and gelatin type B are used, the
molar ratio is 2:1 to 1:2; and when low Bloom gelatin and alginate
are used, the molar ratio is 3:1 to 8:1.
[0138] Processing aids can be included in the shell material (e.g.,
primary or outer shells).
[0139] Processing aids can be used for a variety of reasons. For
example, they may be used to promote agglomeration of the primary
microcapsules, stabilize the emulsion system, improve the
properties of the outer shells, control microcapsule size and/or to
act as an antioxidant. In one aspect, the processing aid can be an
emulsifier, a fatty acid, a lipid, a wax, a microbial cell (e.g.,
yeast cell lines), a clay, or an inorganic compound (e.g., calcium
carbonate). Not wishing to be bound by theory, these processing
aids can improve the barrier properties of the microcapsules. In
one aspect, one or more antioxidants can be added to the shell
material. Antioxidant properties are useful both during the process
(e.g. during coacervation and/or spray drying) and in the
microcapsules after they are formed (i.e. to extend shelf-life,
etc). Preferably a small number of processing aids that perform a
large number of functions can be used. In one aspect, the
antioxidant can be a phenolic compound, a plant extract, or a
sulphur-containing amino acid. In one aspect, ascorbic acid (or a
salt thereof such as sodium or potassium ascorbate) can be used to
promote agglomeration of the primary microcapsules, to control
microcapsule size and to act as an antioxidant. The antioxidant can
be used in an amount of about 100 ppm to about 12,000 ppm, or from
about 1,000 ppm to about 5,000 ppm. Other processing aids such as,
for example, metal chelators, can be used as well. For example,
ethylene diamine tetraacetic acid can be used to bind metal ions,
which can reduce the catalytic oxidation of the loading
substance.
[0140] In one aspect, the primary microcapsules (primary shells)
have an average diameter of about 40 nm to about 10 .mu.m, 0.1
.mu.m to about 10 .mu.m, 1 .mu.m to about 10 .mu.m, 1 .mu.m to
about 8 .mu.m, 1 .mu.m to about 6 .mu.m, 1 .mu.m to about 4 .mu.m,
or 1 .mu.m to about 2 .mu.m, or 1 .mu.m. In another aspect, the
multicore microcapsules can have an average diameter of from about
1 .mu.m to about 2000 .mu.m, 20 .mu.m to about 1000 .mu.m, from
about 20 .mu.m to about 100 .mu.m, or from about 30 .mu.m to about
80 .mu.m. In another aspect, the single-core microcapsules have an
outer diameter of from 1 .mu.m to 2,000 .mu.m.
[0141] The microcapsules described herein generally have a
combination of high payload and structural strength. For example,
payloads of loading substance can be from 20% to 90%, 50% to 70% by
weight, or 60% by weight of the single or multicore
microcapsules.
[0142] In one aspect, the methods disclosed in U.S. Patent
Application Publication No. 2003/0193102, which is incorporated by
reference in its entirety, can be used to encapsulate the chromium
compounds described herein. It is also contemplated that one or
more additional shell layers can be placed on the outer shell of
the single or multicore microcapsules. In one aspect, the
techniques described in International Publication No. WO
2004/041251 A1, which is incorporated by reference in its entirety,
can be used to add additional shell layers to the single and
multicore microcapsules.
[0143] Targeted Delivery
[0144] The disclosed liposomes and microcapsules can be targeted to
a particular cell type, such as islets cells, via antibodies,
receptors, or receptor ligands. The following references are
examples of the use of this technology to target specific tissue
(Senter, et al., Bioconjugate Chem 2:447-51, 1991; Bagshawe, Br J
Cancer 60:275-81, 1989; Bagshawe, et al., Br J Cancer 58:700-3,
1988; Senter, et al., Bioconjugate Chem 4:3-9, 1993; Battelli, et
al., Cancer Imnunol Immunother 35:421-5, 1992; Pietersz and
McKenzie, Immunolog Reviews 129:57-80, 1992; and Roffler, et al.,
Biochem Pharmacol 42:2062-5, 1991). These techniques can be used
for a variety of other specific cell types.
Foodstuffs
[0145] Also disclosed herein are foodstuffs comprising any of the
microcapsules and emulsions disclosed herein. By "foodstuff" is
meant any article that can be consumed (e.g., eaten, drank, or
ingested) by a subject. In one aspect, the microcapsules can be
used as nutritional supplements to a foodstuff. For example, the
microcapsules and emulsions can be loaded with vitamins, omega-3
fatty acids, and other compounds that provide health benefits. In
one aspect, the foodstuff is a baked good, a pasta, a meat product,
a frozen dairy product, a milk product, a cheese product, an egg
product, a condiment, a soup mix, a snack food, a nut product, a
plant protein product, a hard candy, a soft candy, a poultry
product, a processed fruit juice, a granulated sugar (e.g., white
or brown), a sauce, a gravy, a syrup, a nutritional bar, a
beverage, a dry beverage powder, a jam or jelly, a fish product, or
pet companion food. In another aspect, the foodstuff is bread,
tortillas, cereal, sausage, chicken, ice cream, yogurt, milk, salad
dressing, rice bran, fruit juice, a dry beverage powder, rolls,
cookies, crackers, fruit pies, or cakes.
Methods of Use:
[0146] The compounds disclosed herein also have a wide variety of
uses. In the disclosed compounds, the one or more fatty acids are
bonded to a benzenediol derivative and are therefore an integral
part of the complex. Thus, while not wishing to be bound by theory,
it is believed that the fatty acids (e.g., DHA, DPA, and/or EPA)
play at least two roles, i.e., they make the benzenediol
biologically available and they also contribute with their inherent
biological activity. Thus, the disclosed compounds (including the
nutritional supplements, pharmaceutical formulations,
microcapsules, liposomes, and foodstuffs) can deliver fatty acids
(e.g., omega-3 fatty acids), lowering triglycerides and influencing
prevention or treatment of neurodegenerative diseases (Calon, et
al., Neuron 43:633-45, 2004), and benzenediol derivatives like
CoQ.sub.10, a cofactor with a beneficial effect on cardiovascular
and central nervous system health.
[0147] In one particular aspect, disclosed herein are methods of
lowering total cholesterol levels, triglyceride levels, and
increasing HDL levels, or a combination thereof in a subject by
administering an effective amount of any of the compounds described
herein (e.g., Formula I or IV) to the subject. In still another
aspect, disclosed herein are methods of improving insulin
sensitivity in a subject by administering an effective amount of
any of the compounds described herein to the subject. In a further
aspect, disclosed herein are methods of reducing hyperglycemia in a
subject by administering an effective amount of any of the
compounds described herein to the subject. In yet another aspect,
disclosed herein are methods of reducing hypercholesterolemia in a
subject by administering an effective amount of any of the
compounds described herein to the subject.
[0148] Also disclosed herein, in one aspect, are methods of
preventing a mitochondrial condition or disease in a subject by
administering an effective amount of any of the compounds described
herein to the subject. An example of a mitochondrial condition
includes, but is not limited to, mitochondriopathy.
Mitochondriopathy can be characterized by a CoQ.sub.10 deficiency,
ubiquinone-cytochrome c oxidoreductase deficiency, cytochrome c
oxidase deficiency, chronic progressive external opthalmoplegia
syndrome, age-related macular degeneration, neuropathy, ataxia, or
retinis Pigmentosa.
[0149] In another aspect, disclosed herein are methods of
increasing circulation in a subject by administering an effective
amount of any compound comprising any of the compounds described
herein to the subject. In still another aspect, disclosed herein
are methods of increasing the immune system in a subject by
administering an effective amount of any compound comprising any of
the compounds described herein to the subject. Principles and
examples of use of immunostimulants and immunomodulators are
described for instance in: "Immunostimulants now and tomorrow"
(Azuma I, Jolles G, eds.), Japan ScientificSocieties Press, Tokyo,
1987; Hadden J W (1992) "Classification of immunotherapeutic
agents. In: Developments of Biological Standardization," Vol. 77,
(eds Brown F, Revillard J P): 5-15; Karger, Basel; Galeotti M
(1998) "Some aspects of the application of immunostimulants and a
critical review of methods for their evaluation" J Appl Ichtuol
189-199; Halperin S A, Smith B S, Nolan C, Shay J, Kralovec J
(2003) "Randomized, double-blind, placebo-controlled trial of the
safety and immunostimmulatory effect of a Chlorella-derived food
supplement in healthy adults undergoing influenza immunization" Can
Med Assoc J 169: 111-117), which are incorporated by reference in
their entireties. In yet another aspect, disclosed herein are
methods of reducing the side effects of chemotherapy in a subject
by administering an effective amount of any compound comprising any
of the compounds described herein to the subject. In still another
aspect, disclosed herein are methods of treating or preventing
degenerative heart disease in a subject by administering an
effective amount of any compound comprising any of the compounds
described herein to the subject.
[0150] Further, disclosed herein are methods of treating other
conditions or diseases in a subject by administering an effective
amount of any compound comprising Formula I to the subject. Such
other conditions or diseases include, but are not limited to,
cystic fibrosis, asthma, periodontal (gum) disease, Alzheimer's
disease, poor athletic performance, breast cancer, chronic
obstructive pulmonary disease (COPD), HIV, male infertility,
insulin resistance syndrome (Syndrome X), lung cancer, and prostate
cancer.
[0151] The disclosed compounds herein can be used neat or in
combination with some other component. For example, the compounds
can be used in the disclosed methods in the form of any of the
nutritional supplements disclosed herein. In another example, the
compounds can be used in the disclosed methods in the form of any
of the pharmaceutical formulations disclosed herein. In still
another example, the compounds can be encapsulated in any of the
microcapsules or liposomes disclosed herein, or incorporated into
any foodstuff disclosed herein and used in the disclosed
methods.
[0152] It is contemplated that the methods disclosed herein can be
accomplished by administering various forms of the compounds
disclosed herein. For example, one can administer any of the
pharmaceutical formulations with any of the foodstuffs disclosed
herein. In another example, one can administer any of the
microcapsules with any of the nutritional supplements disclosed
herein. In yet another example, one can administer any of the
pharmaceutical formulations with any of the microcapsules and
nutritional supplement disclosed herein, and the like.
[0153] Dosage
[0154] When used in the above described methods or other
treatments, or in the nutritional supplements, pharmaceutical
formulations, microcapsules, liposomes, or foodstuffs disclosed
herein, an "effective amount" of one of the disclosed compounds can
be employed in pure form or, where such forms exist, in
pharmaceutically acceptable salt form and with or without a
pharmaceutically acceptable excipient, carrier, or other
additive.
[0155] The specific effective dose level for any particular subject
will depend upon a variety of factors including the condition or
disease being treated and the severity of the condition or disease;
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the subject; the time of administration; the route of
administration; the rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed and like
factors well known in the medical arts. For example, it is well
within the skill of the art to start doses of the compound at
levels lower than those required to achieve the desired therapeutic
effect and to gradually increase the dosage until the desired
effect is achieved. If desired, the effective daily dose may be
divided into multiple doses for purposes of administration.
Consequently, single dose compositions may contain such amounts or
submultiples thereof to make up the daily dose.
[0156] The dosage can be adjusted by the individual physician or
the subject in the event of any counterindications. Dosage can
vary, and can be administered in one or more dose administrations
daily, for one or several days. Guidance can be found in the
literature for appropriate dosages for given classes of
pharmaceutical products. A typical daily dosage of the compounds
disclosed herein used alone might range from about 10 mg to up to
500 mg (benzenediol content only) or more per day, depending on the
factors mentioned above.
[0157] Administration and Delivery
[0158] In one aspect, disclosed herein are uses of a microcapsule
to deliver a loading substance to a subject, wherein the
microcapsule contains any of the compounds disclosed herein. Also
disclosed are methods for delivering a compound comprising Formula
I (e.g., Formula IV) to a subject by administering to the subject
any of the microcapsules disclosed herein. Further, disclosed are
methods for delivering a compound disclosed herein to a subject by
administering to the subject any of the nutritional supplements,
pharmaceutical formulations, liposomes, and/or foodstuffs disclosed
herein.
[0159] The compounds disclosed herein (including nutritional
supplements, microcapsules, liposomes, and pharmaceutical
formulations) can be administered orally, parenterally (e.g.,
intravenously), by intramuscular injection, by intraperitoneal
injection, transdermally, extracorporeally, topically or the like,
including topical intranasal administration or administration by
inhalant. As used herein, "topical intranasal administration" means
delivery of the compositions into the nose and nasal passages
through one or both of the nares and can comprise delivery by a
spraying mechanism or droplet mechanism, or through aerosolization
of the nucleic acid or vector. Administration of the compositions
by inhalant can be through the nose or mouth via delivery by a
spraying or droplet mechanism. Delivery can also be directly to any
area of the respiratory system (e.g., lungs) via intubation.
EXAMPLES
[0160] The following examples are set forth below to illustrate the
methods and results according to the disclosed subject matter.
These examples are not intended to be inclusive of all aspects of
the subject matter disclosed herein, but rather to illustrate
representative methods and results. These examples are not intended
to exclude equivalents and variations of the present invention
which are apparent to one skilled in the art.
[0161] Efforts have been made to ensure accuracy with respect to
numbers (e.g., amounts, temperature, etc.) but some errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, temperature is in .degree. C. or is at
ambient temperature, and pressure is at or near atmospheric. There
are numerous variations and combinations of reaction conditions,
e.g., component concentrations, desired solvents, solvent mixtures,
temperatures, pressures and other reaction ranges and conditions
that can be used to optimize the product purity and yield obtained
from the described process. Only reasonable and routine
experimentation will be required to optimize such process
conditions.
Example 1
Physical Blending of CoQ.sub.10 and Fish Oil or Fish Oil
Concentrates
[0162] CoQ.sub.10 was solubilized in 0355 EE (fish oil concentrate
in ethylester form containing 3% EPA and 55% DHA), 4020EE (fish oil
concentrate in ethylester form containing 40% EPA and 20% DHA) and
1812TG (purified fish oil containing 18% EPA and 12% of DHA) and
the final solubility was examined under different conditions and
time of storage. All of these starting oils were manufactured by
Ocean Nutrition Canada, Mulgrave, NS). The basic results are listed
in the Table 4.
TABLE-US-00004 TABLE 4 Solubility of CoQ.sub.10ox in selected fish
oil products Solubility Solubility Solubility of CoQ.sub.10 of
CoQ.sub.10 of CoQ.sub.10 in 0355EE in 4020EE in 1812TG No Heating
Heating Heating Prior Prior Prior Storage Storage Storage
Solubility/ Confirmed Confirmed Confirmed Storage solubility.
solubility. solubility. (%, w/w) (%, w/w) (%, w/w) Solubility at RT
6.6 ND ND Storage at 4.degree. C. 2.5 ND ND for 24 h Solubility at
27% 9 11 50.degree. C. Storage at 4.degree. C. 3.2% 5.7 <2.9
[0163] Solubilization of CoQ.sub.10ox in the tested fish oil and
concentrates is clearly very limited.
Example 2
Direct Esterification of CoQ.sub.10
[0164] CoQ.sub.10 exists primarily in its oxidized ubiquinone form
(CoQ.sub.10ox). However, it was tested whether the concentration of
the reduced form in a normal CoQ.sub.10ox sample would be high
enough to initiate the coupling and progressively form more and
more conjugate due to the equilibrium shift, (e.g., that the
reaction would be under thermodynamic control). Although it is
generally accepted that for acylation of phenols, basic catalysis
is more effective, these reactions were performed using both acidic
and basic catalysis, initially with NaHSO.sub.4 or K.sub.2CO.sub.3,
respectively. The molar ratio of free fatty acid over CoQ.sub.10
initially used was 2:1 and 5:1, respectively, and the reactions
were performed at 120.degree. C. An H.sub.3BO.sub.3/H.sub.2SO.sub.4
combination and carbodiimides were also used, including
PS-carbodiimide, a resin bound coupling agent, (both at room
temperature and under reflux).
[0165] To improve the yields of the acylation, CoQ.sub.10ox was
converted to the corresponding reduced form (CoQ.sub.10red) by
NaBH.sub.4, and later even more conveniently by hydrogen generated
by Zn from AcOH. High yields were achieved by reacting CoQ.sub.10
with free fatty acid that was first converted to the corresponding
chloride with SOCl.sub.2. It was found that the use of nitrogen
base such as Et.sub.3N was helpful to achieve good conversions. The
highest yields were accomplished using P.sub.2O.sub.5 (phosphoric
acid anhydride). While not wishing to be bound by theory, it was
assumed that a mixed anhydride of the formula (DHA-COO).sub.2PO is
the reaction intermediate. In addition, excess catalyst can drive
the equilibrium by capturing the produced water.
Example 3
Preparation of CoQ.sub.10red
[0166] Ten grams (11.57 mmol) of CoQ.sub.10ox was stirred with 20 g
zinc powder in 200 mL glacial acetic acid under reflux for 1 hour
(h) at 65-70.degree. C. The residual acetic acid was then
evaporated and the mixture extracted 3 times with hexane,
centrifuged, filtered and concentrated. The product was obtained in
a quantitative yield, in a form of light yellow syrup that quickly
crystallized yielding white crystals. The product was stored under
nitrogen.
Preparation of Omega-3-CoQ.sub.10 Conjugates
Example 4
[0167] A mixture of 3.93 g (11.57 mmol) 4020FFA (Free Fatty Acid,
prepared by hydrolysis of 4020EE, a product of Ocean Nutrition
Canada, Mulgrave, NS) with 10 mL thionyl chloride was refluxed
until no more HCl was produced (approximately 2 h) and then excess
thionyl chloride was evaporated. The product (FFA-Cl) was in a form
of dark brown liquid and obtained in a quantitative yield.
[0168] A mixture of CoQ.sub.10red (10 g, 11.57 mmol) and
triethylamine (1.627 mL, 1.171 g, 11.57 mmol) in 10 mL
CH.sub.2Cl.sub.2 was added to the prepared FFA-Cl. The reaction was
stirred for 5 h at room temperature and pressure with a CaCl.sub.2
trap, then the solvent was evaporated, and the residue was mixed
with 60 mL acetone to precipitate the triethylammonium chloride.
The precipitate was filtered off, acetone evaporated, and the
product reconstituted in hexane. The reaction was monitored by TLC
(hexane/diethyl:ether (6:4)+1% AcOH, and sprayed with 15%
H.sub.2SO.sub.4 in MeOH). The product was isolated from the final
reaction mixture by column chromatography on silica gel using 1%
diethylether in hexane as a solvent. It was obtained in a form of a
yellow liquid and stored in the refrigerator under nitrogen.
Example 5
[0169] A mixture of 5.62 g (18 mmol) of 4020FFA and 3.71 g
dicyclohexyldicarbodimide (DCC) (18 mmol) in 18 mL of hexane was
stirred overnight. Then a mixture f CoQ.sub.10red (0.865 g, 1 mmol)
and triethylamine (0.276 ml, 0.2024 g, 2 mmol) was added to a
portion of the activated free fatty acid (FFA) (0.624 g, 2 mmol).
The reaction was stirred overnight at room temperature, monitored
and the product isolated as described in Example 4.
Example 6
[0170] A solution of reduced CoQ.sub.10red (2.0 g, 2.3 mmol) in
4020FFA (1.7 g 5 mmol) was prepared at 50.degree. C. and
P.sub.2O.sub.5 (1.42 g, 10 mmol) was added. The reaction was then
heated at 50-60.degree. C. for 28 h under vacuum (<7 mbar). The
reaction mixture was removed from the vessel using a mixture of
hexane and chloroform; the extract was evaporated and then
chromatographed as described in Example 4.
Example 7
Analysis
[0171] Mass spectral analysis confirmed synthesis of bifunctional
omega-3-CoQ.sub.10 conjugate. A sample of the reaction mixture was
injected directly into Micromass QTOF mass spectrometer
chromatography using a Waters 2695 HPLC system. A Waters 996 photo
diode array was installed upstream from the mass spectrometer to
monitor the elution profile using ultraviolet absorbance. The
eluent (40% heptane, 20% chloroform, 40% methanol with 0.1%
AcONH.sub.4) flow rate was set to 0.2 ml/min and the sample
injection volume was 5 .mu.L. The mass spec was operated in ESI+
mode to monitor for cationic ammonium adducts of the sample. There
was significant evidence for CoQ.sub.10red conjugated with both EPA
and DHA fatty acids as evidenced from FIGS. 1-3.
* * * * *